7-Oxabicycloheotane carboxylic acid prostaglandin analog intermediates useful in the preparation of anti-thrombotic and anti-vasospastic compounds and method for preparing same

ABSTRACT

A method is provided for preparing carboxylic acid intermediates of the structure ##STR1##

REFERENCE TO OTHER APPLICATIONS

This is a division of application Ser. No. 356,743, filed Dec. 15, 1994,now pending which is a division of application Ser. No. 226,091, filedApr. 20, 1994, now U.S. Pat. No. 5,399,725, which is acontinuation-in-part of application Ser. No. 67,886, filed May 27, 1993,now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel 7-oxabicycloheptane carboxylicacid prostaglandin analog intermediates which may be used to prepare afinal anti-thrombotic--anti-vasospastic product, and to methods forpreparing same.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptylsubstituted heterocyclic amide prostaglandin analogs which arethromboxane A₂ (TXA₂) receptor antagonists or combined thromboxane A₂receptor antagonist/thromboxane synthetase inhibitors useful, forexample, in the treatment of thrombotic and/or vasospastic diseases, andhave good duration of action. Examples of compounds disclosed in Misraet al have the structural formula I ##STR2## and including allstereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

R¹ is hydrogen, lower alkyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl,or amide ##STR3## wherein t is 1 to 12 and R_(a) is lower alkyl, aryl,cycloalkyl, or cycloalkylalkyl);

R² is hydrogen, lower alkyl, aryl, or aralkyl; or R¹ and R² togetherwith the nitrogen to which they are linked may form a 5- to 8-memberedring.

Misra et al disclose that these compounds may be prepared bytransmetallating bromophenylalkyl B ##STR4## by treatment with t-C₄ H₉Li or n-C₄ H₉ Li or subjecting B to a Grignard reaction by treatmentwith Mg, and then condensing with the perhydro benzopyran-3-olderivative or the perhydro benzofuran-1-ol derivative ##STR5## to formthe condensed 7-oxabicycloheptane alcohol compound of the structure Z##STR6## and then subjecting the condensed compound to hydrogenolysis toform the following alcohol ##STR7## Where Pro is thexyldimethylsilyl ort-butyldimethylsilyl, the alcohol is acetylated and the silyl protectinggroup of the so-formed acetate is removed to form the following acetate:##STR8## which is treated with a protecting compound and the acetate isremoved by treatment with aqueous hydroxide or excess methyllithium toform the following alcohol: ##STR9## (where Pro ist-butyldiphenylsilyl). The protected alcohol is subjected to a Jonesoxidation to form the following acid: ##STR10##

The so-formed carboxylic acid intermediate is then employed to make thefinal compound.

In a more preferred procedure, Misra et al disclose protecting thealcohol function of alcohol Z to form the protected alcohol ##STR11##subjecting the protected alcohol to a Jones oxidation and esterificationto form the ester ##STR12## which is made to undergo hydrogenolysis andsubsequent removal of the acetate protecting group bytransesterification to afford the alcohol ##STR13## which is subjectedto a Jones oxidation to form the carboxylic acid intermediate II##STR14##

In an alternative procedure where n is 1, the above carboxylic acidintermediate II is formed by treating D' with acetic anhydride andremoving the protecting group to form the acetate alcohol ##STR15##which is made to undergo a Dess-Martin oxidation to form the aldehyde##STR16## The above aldehyde is oxidized and esterified to thecorresponding acetate ester, deprotected, and subjected to a Jonesoxidation to form carboxylic acid II where n is 1.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, methods are provided forpreparing intermediates for use in the preparation of 7-oxabicycloheptylsubstituted oxazole amide prostaglandin analogs as described hereinafterwhich are useful as anti-thrombotic and anti-vasospastic compounds.

The methods of the invention are outlined in Reaction Schemes 1 to 6 setout hereinafter. ##STR17##

Referring to the above Reaction Schemes, one aspect of the presentinvention includes a method for preparing carboxylic acid startingmaterial IIA ##STR18## wherein R is lower alkyl preferably methyl orethyl. As shown in Reacton Scheme 1, in accordance with the presentinvention, carboxylic acid IIA is prepared from starting aldehyde III(which is a novel compound in accordance with the invention) and ispreferably in substantially enantiomerically pure form, which is made toundergo a Horner-Emmons reaction wherein aldehyde III is treated with aphosphonic diester compound IV in the presence of a base such as1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), or1,5-diazabicyclo-[4.3.0]non-5-ene (DBN), or Hunig's base(diisopropyl-ethylamine), preferably DBU, and an inert organic solventsuch as acetonitrile, tetrahydrofuran (THF), dimethoxyethane or toluene,preferably, acetonitrile, and an alkali metal salt such as lithiumchloride, lithium bromide, or an alkaline earth metal salt such asMgBr₂, or magnesium methoxide, to form the ester V wherein R is loweralkyl such as methyl or ethyl (which is a novel compound in accordancewith the present invention). As shown in Scheme 1, the ester V will beprimarily in the form of the trans isomer.

Alternatively, the Horner-Emmons reaction may be carried out bysubstituting for DBU, as a base, an alkali metal hydride such as sodiumhydride, or lithium bis(trimethylsilyl)amide, or potassium t-amylate, inan inert organic solvent such as tetrahydrofuran, toluene ordimethoxyethane.

In another variation on Scheme 1, the aldehyde III may be homologated toform ester V by treating III with a magnesium salt of a monoalkylmalonate of the structure ##STR19## wherein R^(a) is a lower alkyl, suchas methyl or ethyl, in the presence of THF or other etheral solvent suchas diethyl ether.

The ester V (primarily in the form of the trans isomer) will besubjected to a hydrogenation wherein ester V is treated with hydrogen inthe presence of a hydrogenation catalyst such as Pd(OH)₂ /C or Pd/C, andin the presence of an alcohol solvent such as methanol or ethanol, andan inert organic solvent such as THF, ethyl acetate or dioxane, to formcarboxylic acid IIA.

In an alternative embodiment as shown in Reaction Scheme 2, carboxylicacid intermediate IIA is formed by subjecting aldehyde III to aKnoevenagel reaction where III is treated with malonic acid in thepresence of a base-solvent such as pyridine, 2,6-lutidine or collidine,and a catalytic amount of piperidine, to form acid VI (which is a novelcompound in accordance with the present invention). Acid VI may then beesterified, for example, by reaction with an alkanol, such as methanolor ethanol, in the presence of a strong acid catalyst such as sulfuricacid, p-toluenesulfonic acid or camphorsulfonic acid, to form the esterV. Ester V may then be hydrogenated as described above with respect toReaction Sequence 1, to form carboxylic acid intermediate IIA.

The starting aldehyde III may be prepared, in accordance with thepresent invention, as shown in Reaction Scheme 3 starting with amine VII##STR20## wherein R⁷ is aryl or lower alkyl, preferably phenyl, R⁸ is H,aryl or lower alkyl, preferably H,

R⁹ is H, OH or lower alkyl, preferably OH or H.

However where R⁹ is OH, amine VII will preferably have the structure##STR21##

Amine VII is made to undergo imide formation by dehydration by reactingVII with anhydride VIII in the presence of a weak organic base such astriethylamine, diisopropylethylamine or N-ethylpiperidine, an inertorganic solvent such as THF, toluene or benzene and an acid such asoxalic acid, malonic acid or p-toluenesulfonic acid, to form imide IXwhich is a novel intermediate.

Alternatively, imide IX may be formed by reacting VII with anhydrideVIII in the presence of o, an aromatic solvent such as toluene, benzeneor xylene, preferably at reflux with azeotropic removal of water.

Imide IX is then subjected to an addition reaction by treating IX with ametallated aryl compound of the structure ##STR22## wherein Metal isMgBr or Li. Where Metal is MgBr, such Grignard reagent XA is prepared bydissolving the halide ##STR23## (wherein halide refers to Br or I), inan inert organic solvent, such as THF, dioxane, toluene or t-butylmethylether, and mixing the so-formed solution with magnesium to give the arylGrignard reagent XA.

A cooled solution of imide IX in an inert organic solvent such as THF,t-butylmethyl ether, toluene or dioxane, is mixed with a solution of analkyl (or aryl) magnesium halide such as ethylmagnesium chloride,ethylmagnesium bromide or phenylmagnesium chloride (used only if R⁹ isOH) in the same solvent used for imide IX, followed by the Grignardreagent XA, to form intermediate XI which is reduced, for example, byreaction with a reducing agent such as sodium borohydride, lithiumborohydride or zinc borohydride, in the presence of an alcohol solventsuch as ethanol or methanol, to form amide XII.

Where the metallated aryl compound X to be employed is the aryl lithiumderivative XB and R₉ ═OH, imide IX may be first treated with an alkyllithium compound (R^(a) Li where R^(a) is lower alkyl) such asmethyllithium, ethyllithium or butyllithium, and then with thearyllithium derivative XB ##STR24## in the presence of an inert organicsolvent such as THF, toluene, tert-butylmethyl ether or diethyl ether.The resulting intermediate XIA (same as XI except MgBr is replaced withLi) is reduced as described for XI to form amide XII.

Amide XII is made to undergo lactonization by dissolving XII in tolueneand heating to form the lactone XIIA (which is a novel intermediate)##STR25## which is treated with water and a base such as NaOH, KOH,LiOH, Mg(OH)₂ or Ca(OH)₂ in the presence of an alcohol solvent such asethanol or methanol, to form the salt XIIB (which is a novelintermediate) ##STR26## where M⁺ is a metal ion such as Na⁺, K⁺ and thelike.

XII may be treated with NaOH directly to form salt XIIB.

Salt XIIB is then treated with strong acid such as hydrochloric acid,sulfuric acid, or nitric acid in the presence of an inert organicsolvent, such as THF, isopropanol or dioxane, to form starting aldehydeIII as a single enantiomer as shown.

In a further aspect of the present invention, as seen in Reaction Scheme4, the carboxylic acid IIA intermediate is employed to prepare athromboxane receptor antagonist IA-IC. As seen in Scheme 4, carboxylicacid IIA is subjected to a coupling reaction wherein carboxylic acid IIAin an inert solvent such as toluene, methylene chloride, or1,2-dichloroethane is treated under an inert atmosphere with a catalyticamount of DMF. The resulting mixture is cooled below 0° C. and oxalylchloride or other reagent for acid chloride formation such as thionylchloride is added to form an acid chloride solution. Where thionylchloride is to be employed, carboxylic acid IIA need not be treated withcatalytic DMF.

Amide XIII (prepared as described in Scheme 5) is added to an aqueoussodium bicarbonate solution and an inert organic solvent such as methylethyl ketone, methylene chloride or THF is added to form a biphasicmixture which is cooled to from about 30° to about -10° C. Thepreviously prepared acid chloride solution is added and the mixtureheated to a temperature within the range of from about 40° to about 80°C. to form amide XIV.

Amide XIV is mesylated by treating a solution of amide XIV in DMF orother solvent such as methylene chloride or THF, with an organic basesuch as triethylamine, pyridine or 2,6-lutidine and then whilemaintaining the mixture below about 5° C., methanesulfonyl chloride isadded to form the mesylate XV. Mesylate XV is cyclized by treating XVwith triethylamine or other organic base as set out above, in thepresence of DMF or other solvent as set out above to form oxazoline XVI.

Oxazoline XVI is oxidized using cupric bromide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the presence ofhexamethylenetetramine and an inert organic solvent such as methylenechloride to form oxazole ester IA which is saponified by treatment withstrong base such as NaOH, KOH and the like, in aqueous-organic solventsuch as THF or dioxane, and then is acidified by treatment with strongacid such as HCl, sulfuric acid or trifluoroacetic acid to form oxazoleacid IB. Oxazole acid IB may then be treated with alkali metal alkoxidesuch as sodium methoxide, sodium 2-ethan-hexanoate or sodium ethoxide,in the presence of inert organic solvent such as acetone, THF or ethylacetate, and an alcohol such as methanol or ethanol to form oxazole saltIC.

Referring to Reaction Scheme 5, the amide XIII (used in Scheme 4) isprepared by reacting an aqueous solution of L-serine and NaOH withbenzyl chloroformate to form carbobenzyloxy-L-serine which is treatedwith DBU under an inert atmosphere. Thereafter trimethylacetyl chlorideand amine XVII are added to form amide XVIII which is deprotected bytreatment with H₂ and Pd/C in the presence of an alcohol solvent, suchas ethanol or methanol, to form amide XIX which is treated with oxalicacid or another acid such as HCl or trifluoroacetic acid in the presenceof alcohol solvent such as ethanol or methanol to form amide XIII.

In the amine XVII, R¹ and R² are as defined in U.S. Pat. No. 5,100,889which is incorporated herein by reference.

Thus, R¹ is hydrogen, lower alkyl, aralkyl, aryl, cycloalkyl,cycloalkylalkyl, or amide ##STR27## wherein t is 1 to 12 and R_(a) islower alkyl, aryl, cycloalkyl, or cycloalkylalkyl); and

R² is hydrogen, lower alkyl, aryl, or aralkyl; or R¹ and R² togetherwith the nitrogen to which they are linked may form a 5- to 8-memberedring.

R¹ is preferably lower alkyl such as n-pentyl, aryl such as phenyl,halophenyl such as 4-chlorophenyl, or cyclohexylalkyl, such ascyclohexylbutyl.

R² is preferably H or phenyl.

The novel intermediates of the invention have the structures ##STR28##wherein R⁵ is --CHO or --CH═CH--CO₂ R⁶ wherein R⁶ is H or alkyl (A. willpreferably be in enantiomerically pure form as shown and may be preparedin such pure form employing the procedures described herein); ##STR29##including all stereoisomers thereof, wherein R⁷ is aryl or lower alkyl,preferably phenyl,

R⁸ is H, aryl or lower alkyl, preferably H and

R⁹ is H, OH or lower alkyl, preferably OH or H.

In compound B, where R⁹ is OH, compound B will preferably comprise theenantiomer ##STR30##

In Compound B where R⁹ is not OH, compound B will preferably comprisethe enantiomer ##STR31##

DETAILED DESCRIPTION OF THE INVENTION

In carrying out the method of the invention as shown in Scheme 1 forpreparing carboxylic acid IIA, the Horner-Emmons reaction is carried outin the presence of base and optionally an alkali or alkaline earth metalsalt such as a lithium halide, for example, lithium chloride, lithiumbromide, lithium iodide or magnesium bromide, employing a molar ratio ofphosphonic acid IV: aldehyde III of within the range of from about 1:1to about 1.5:1, preferably from about 1:1 to about 1.2:1, under an inertatmosphere such as argon or nitrogen, to form the ester V in a ratio oftrans:cis isomers of within the range of from about 14:1 to about 36:1.

Where ester V is formed by homologation of aldehyde III employing themagnesium salt of a monoalkylmalonate (IVA), the magnesium salt IVA willbe employed in a molar ratio to aldehyde III of within the range of fromabout 1:1 to about 2:1.

The so-formed ester V is then hydrogenated preferably employingPearlman's catalyst (Pd(OH)₂ /C) to form the carboxylic acid IIA. Othercatalysts, such as palladium on carbon may be employed in carrying outthe hydrogenation step.

Alternatively, as seen in Scheme 2, the aldehyde III may be subjected toa Knoevenagel reaction employing a molar ratio of malonic acid:aldehydeIII of within the range of from about 6:1 to about 3:1, preferably fromabout 5:1 to about 4:1. The reaction is carried out at a temperaturewithin the range of from about 60° to about 100° C. The resulting acidVI is esterified with an alkanol, preferably methanol or ethanol,employing conventional techniques to form the ester V which may behydrogenated as described above to form carboxylic acid IIA.

The aldehyde III is prepared as shown in Scheme 3 wherein the amine VIIis reacted with anhydride VIII employing a molar ratio of VII:VIII ofwithin the range of from about 1:1 to about 1.5:1, preferably from about1.2:1 to about 1.0:1. The reaction, including oxalic acid or other acidand base and solvent, is carried out at a temperature within the rangeof from about 40° to about 100° C., preferably from about 60° to about80° C.

Where toluene is employed in place of base and oxalic acid, the reactionof VII and VIII is carried out at a temperature within the range of fromabout 80° to about 120° C., preferably from about 100° to about 115° C.

The resulting imide IX is then subjected to an addition reaction, suchas a Grignard reaction, to ultimately form aldehyde III of desiredoptical purity.

In carrying out the Grignard reaction, the aryl Grignard reagent XA isprepared by treating a solution of 2-(2-halophenyl)-1,3-dioxolane (wherehalo is Br or I) in THF or other inert organic solvent such as dioxaneor t-butylmethyl ether, with magnesium, preferably in the form of Mgturnings, employing a molar ratio of Mg:2-(2-bromophenyl)-1,3-dioxolaneof within the range of from about 2:1 to about 1.0:1, preferably fromabout 1.1:1 to about 1.5:1.

If imide IX has R₉ ═OH, then imide IX is first treated with an alkyl- oraryl-magnesium halide (e.g. Cl⁻, Br⁻ or I⁻), preferably ethyl magnesiumchloride, employing a molar ratio of imide IX to ethylmagnesium halidewithin the range of from about 1:1.1 to 1:1. The so-formed aryl Grignardreagent XA is then mixed with the reaction solution employing a molarratio of imide IX to aryl Grignard reagent XA of within the range offrom about 1:4 to about 1:1, preferably from about 1:1.2 to about 1:2.5.If imide IX has R₉ ≠OH then the so-formed aryl Grignard reagent XA ismixed with imide IX employing a molar ratio of imide IX to aryl Grignardreagent XA of within the range of from about 1:3 to about 1:1.1,preferably from about 1:1.4 to about 1:2.

To achieve desired optical purity in the final aldehyde III, it ispreferred that the Grignard reaction be carried out employingethylmagnesium chloride in a molar ratio to imide IX of within the rangeof from about 0.9:1 to about 1.2:1, preferably from about 1.0:1 to about1.1:1. The ethyl-magnesium chloride will be employed in solution,preferably in THF, at a concentration of within the range of from about1.0M to about 2.5M, preferably from about about 1.5M to about 2.0M. Thereaction of X with imide IX will be carried out at a temperature withinthe range of from about -78° C. to about 40° C., preferably from about-40° to about 20° C.

The ratio of desired to undesired diastereomers obtained using the aboveconditions will range from about 90:10 to >99:1.

Ethylmagnesium bromide may be employed in place of ethylmagnesiumchloride with a resulting decrease in ratio of desired to undesireddiastereomers for imides IX where R₉ ═OH.

Where the addition reaction of imide IX having R₉ ═OH to formintermediate XI is carried out employing the metallated aryl compound Xwhere the metal is Li, imide IX is first treated with the alkyl lithiumcompound R^(a) Li employing a molar ratio of R^(a) Li:IX of within therange of from about 0.9:1 to about 1.2:1. The imide IX is then treatedwith the Li aryl compound XB employing a molar ratio of XB:IX of withinthe range of from about 1:1 to about 1:3.

The above reactions are carried out at a temperature within the range offrom about -78° C. to about 40° C.

The alcohol XI resulting from the addition reaction, such as theGrignard reaction is then reduced employing a molar ratio of reducingagent:XI of within the range of from about 0.5:1 to about 3:1,preferably from about 0.8:1 to about 2:1.

The resulting amide XII is made to undergo lactonization employing amolar ratio of toluene:XII of within the range of from about 20:1 toabout 10:1, preferably from about 16:1 to about 12:1. The toluene-XIImixture is heated to a temperature of within the range of form about 60to about 120° C., preferably from about 110 to about 115° C. to formlactone XIIA. Lactone XIIA is treated with base:alcohol in a molar ratioof within the range of from about 0.1:1 to about 1.0:1, preferably fromabout 0.2:1 to about 0.4:1. The mixture is extracted with ethyl acetateand the aqueous layer is acidified with strong acid to achieve a pH ofwithin the range of from about 1 to about 2.

The ethyl acetate wash may be treated with an acid such as oxalic acidand used to recrystallize starting material VII such as(S)-phenyl-glycinol•(CO₂ H)₂.

The starting amine compounds VII wherein R⁹ is other than OH are knownin the art or may be prepared by conventional procedures.

Where in the starting amine compound VII, R⁹ is OH, such compound may beprepared by reduction of an amino acid of the structure ##STR32##employing a mixture of sodium borohydride and sulfuric acid, orpreferably NaBH₄ and BF₃ etherate (BF₃ --O(C₂ H₅)₂), in the presence ofan inert organic solvent, such as THF or dimethoxyethane at atemperature of within the range of from about 60 to about 100° C.

The imide IX may also be prepared as shown in Reaction Schemes 6A, 6Band 6C.

In Reaction Scheme 6A, imide IX is prepared starting with maleicanhydride which is reacted with furan, under an inert atmosphere such asargon, employing a molar ratio of furan:maleic anhydride of within therange of from about 4:1 to about 20:1, preferably from about 5:1 toabout 7:1, to form anhydride VIIa.

Anhydride VIIa is mixed with inert organic solvent such as n-butylacetate, t-butyl acetate or xylene, under an inert atmosphere such asargon, and the resulting mixture is chilled and then reacted with amixture of amine base such as triethylamine, diisopropylethylamine, ortributylamine, and amine VII, which includes at least one chiral center(which is attached directly to the nitrogen of the amine), employing amolar ratio of anhydride VIIa:amine VII of within the range of fromabout 0.9:1 to about 1:1, preferably about 1:1, to form amine XX (as amixture of diastereomers). Amine XX is then reduced by reaction withhydrogen in the presence of a catalyst such as Pd--C, Pd--BaSO₄ or Pt--Cto form amine XXII. The reaction mixture is filtered to remove catalystand heated at a temperature within the range of from about 150° to about170° C., preferably from about 155° to about 160° C., to remove aminebase and water to form imide IX.

In a preferred embodiment, in amine vII, R⁷ is phenyl, and R⁸ and R⁹ areeach hydrogen.

In Reaction Scheme 6B, imide IX is prepared by a Diels-Alder reaction ofmaleimide XXIII (which includes at least one chiral center) with furanemploying a molar ratio of furan:XXIII of within the range of from about2.5:1 to about 10:1, preferably from about 3:1 to about 4:1, in thepresence of a Lewis acid, such as AlCl₃, AlBr₃, FeBr₃, TICl₄, or SnCl4,and inert organic solvent such as methylene chloride, dichloroethane ortoluene, under an inert atmosphere such as argon, to form the exo adductXXV. Exo adduct XXV is reduced by reaction with hydrogen in the presenceof a catalyst such as Pd/C, Pd--BaSO₄, or Pt--C, in the presence ofinert organic solvent, such as ethyl acetate, toluene ortetrahydrofuran, to form imide IX.

As shown in Reaction Scheme 6B, endo compound XXVA is formed togetherwith exo compound XXV. During the reaction endo compound XXVA undergoesa selective retro Diels-Alder reaction to form starting materials furanand imide XXIII which are further recycled to produce the thermodynamicexo product XXV.

The maleimide XXIII is prepared by reaction of maleic anhydride andamine VII (which includes at least one chiral center directly attachedto the nitrogen of the amine) in the presence of an amine base such astriethyl amine or diisopropylethyl amine, acetic anhydride or othercyclizing agent such as propionic anhydride, and an inert organicsolvent such as THF, ethylene glycol, dimethyl ether or toluene, at atemperature of within the range of from about 70° to about 120° C.,preferably from about 80° to about 90° C., employing a molar ratio ofmaleic anhydride:amine VII of within the range of from about 0.9:1 toabout 1.1:1, preferably about 1:1.

Maleimide XXIII may also be prepared from acid VIIB ##STR33## bytreating VIIB with an amine base such as diisopropylamine, triethylamineor tributylamine in the presence of a silylating agent such ashexamethyldisilazane (HMDS), chlorotrimethylsilane (TMSCl),bissilylacetamide (BSA) or bissilylurea (BSU) and acetonitrile, n-butylacetate or toluene, to form maleimide XXIII.

In carrying out the above reactions to form maleimide XXIII, the aminebase will be employed in a molar ratio to VIIB of within the range offrom about 1.2:1 to about 1.1:1, preferably about 1:1, while thesilylating agent will be employed in a molar ratio to VIIB of within therange of from about 2:1 to about 1:1. These reactions are carried out ata temperature within the range of from about 60° to about 110° C.

The acid VIIB is prepared by reacting amine VII with maleic anhydride##STR34## in the presence of acetonitrile, tetrahydrofuran (THF) orethylacetate employing a molar ratio of maleic anhydride to VII ofwithin the range of from about 0.9:1 to about 1.05:1, preferably about1:1.

In Reaction Scheme 6C, imide XXXI is prepared in the latter part ofScheme 6C as follows: compound XXIX is reacted with hydrogen in thepresence of a transition metal catalyst such as Pd/C, Pd--BaSO₄ orPt--C, to form XXX, followed by deacetylation with alkali metalcarbonate, such as K₂ CO₃, Li₂ CO₃ or Na₂ CO₃, preferably K₂ CO₃, toform XXXI.

Imide XXXI may then be employed to prepare compounds of formulae IA, IBand IC following Reaction Schemes 3, 1 and 4.

The compound XXIX is prepared as shown in the early part of ReactionScheme 6C, wherein amine alcohol VIIA (which includes at least onechiral center and R⁷ is preferably phenyl) is reacted with a silylatingagent (employing a molar ratio of silylating agent:VIIA of within therange of from about 2.5:1 to about 5:1) such as bistrimethylsilyl urea(BSU), TMSCl/Et₃ N, HMDS or bissilylacetamide (BSA), preferably BSU andan inert organic solvent such as tetrahydrofuran, glyme, EtOAc, CH₃ CNor toluene, at a temperature within the range of from about 50° to about70° C. The maleic anhydride (employing a molar ratio of anhydride:VIIAof within the range of from about 0.75:1 to about 3:1) is added and themixture is heated to a temperature of within the range of from about 50°to about 70° C., to form silylated compound XXVII. XXVII is cyclized bytreating with water and a catalyst for desilylation, such asn-tetrabutyl ammonium fluoride (TBAF), potassium fluoride or cesiumfluoride, in the presence of a cyclizing agent such as acetic anhydrideor propionic anhydride, and an amine base such as triethylamine,diisopropylethylamine or tributylamine, to form compound XXVIII.Compound XXVIII is reacted with furan (employing a molar ratio offuran:XXVIII of within the range of from about 30:1 to about 15:1) inthe presence of inert organic solvent such as dichloromethane,dichloroethane or toluene to form predominantly the exo compound XXIXand endo compound XXIXA in minor amount. As shown, endo compound XXIXAin the presence of Lewis acid, such as any of the Lewis acids describedabove in Reaction Scheme 6B, forms exo compound XXIX.

The desilylating agent, such as TBAF, will be employed in a molar ratioto silylated compound XXVII of within the range of from about 0.05:1 toabout 0.3:1, preferably from about 0.1:1 to about 0.2:1, while thecyclizing agent, such as the acid anhydride will be employed in a molarratio to silylated compound XXVII of within the range of from about 5:1to about 20:1, preferably from about 7:1 to about 10:1, and the basewill be employed in a molar ratio to silylated compound XXVII of withinthe range of from about 5:1 to about 15:1, preferably from about 7:1 toabout 10:1.

In a preferred embodiment in amine VIIA, R⁷ is phenyl, and R⁸ ishydrogen.

Alternatively, compound XXVIII may be prepared by treating amine alcoholVIIA with maleic anhydride (employing a molar ratio of alcohol:VIIA ofwithin the range of from about 1.2:1 to about 1.1:1) in the presence ofan inert organic solvent such as THF, toluene, monoglyme orethylacetate, under an inert atmosphere such as argon at a temperaturewithin the range of from about 20° to about 50° C., to form amide acidVIIC. ##STR35##

The amide acid VIIC is cyclized by treatment with a cyclizing agent suchas acetic anhydride or propionic anhydride (employing a molar ratio ofanhydride:VIIC of within the range of from about 7:1 to about 5:1) andamine base such as triethylamine or diisopropylethylamine, in thepresence of an inert organic solvent such as THF, toluene, monoglyme orethylacetate, at a temperature within the range of from about 70° toabout 110° C., to form compound XXVIII.

The halide compound ##STR36## (for example,2-(2-bromophenyl)-1,3-dioxolane) employed to prepare Grignard reagent XAused in Scheme 3 is prepared by reaction of the aldehyde ##STR37## withethylene glycol and p-toluenesulfonic acid in the presence of anaromatic solvent such as toluene, benzene or xylene, under an inertatmosphere such as nitrogen, at a temperature within the range of fromabout 80° to about 150° C., preferably at reflux.

In carrying out the preparation of the thromboxane receptor antagonistproducts IB and IC, as shown in Scheme 4, amide XIII is employed in amolar ratio to acid IIA of within the range of from about 1.5:1 to about1:1, preferably from about 1.1:1 to about 1:1, to form amide XIV. AmideXIV is mesylated employing a molar ratio of methanesulfonyl chloride:XIVof within the range of from about 2:1 to about 1:1, preferably fromabout 1.3:1 to about 1:1 and a temperature within the range of fromabout -20° to about 60° C., preferably from about 0° to about 25° C.

The resulting mesylate XV is cyclized employing a molar ratio oftriethylamine or other organic base:XV of within the range of from about4:1 to about 2:1, preferably from about 3.5:1 to about 2.5:1, to formoxazoline XVI. Other organic bases which may be employed includediisopropylethylamine, pyridine or 2,6-lutidine.

The cupric bromide oxidation of oxazoline XVI is carried out at atemperature of within the range of from about 20° C. to about 70° C.,employing a molar ratio of cupric bromide to oxazoline XVI of within therange of from about 2:1 to about 6:1 and a molar ratio of cupric bromideto DBU of within the range of from about 1:1 to about 1:3 in an inertsolvent, preferably methylene chloride or acetonitrile. The oxidation ispreferably carried out in the presence of a base such ashexamethylenetetramine which is such as lower alkyl,trifluoromethyl,halogen (Cl, Br, I or F), alkylsulfonyl, and/or arylsulfonyl.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinrefers to lower alkyl groups as discussed above having an arylsubstituent, such as benzyl.

The term "lower alkoxy", "alkoxy" or "aralkoxy" includes any of theabove lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" as used herein refers to Cl, Br, F or I,with Cl preferred.

The final compounds IB and IC prepared by the method of this inventionare thromboxane receptor antagonists and as such are useful asinhibitors of thromboxane receptor mediated actions. The term"thromboxane receptor antagonist" includes compounds which are so-calledthromboxane A² receptor antagonists, thromboxane A² antagonists,thromboxane A² /prostaglandin endoperoxide antagonists, TP-receptorantagonists, or thromboxane antagonists.

The compounds prepared by the method of the invention are alsothromboxane synthetase inhibitors and thus are useful as inhibitors ofthromboxane production.

Examples of various utilities of the compounds prepared by the method ofthe invention are set out in U.S. Pat. No. 5,100,889.

The following Examples represent preferred embodiments of the presentinvention. Unless otherwise indicated, all temperatures are expressed indegrees Centigrade.

EXAMPLE 1[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde

A. (S)-β-Aminobenzeneethanol

A one-liter three-necked flask equipped with a mechanical stirrer,reflux condenser and an addition funnel was charged with sodiumborohydride (18.7 g, 0.495 mole), (S)-(+)-2-phenylglycine (Aldrich) (30g, 0.198 mole) and THF (200 mL). The slurry was stirred vigorously atroom temperature under argon. The addition funnel was charged with borontrifluoride etherate (54 mL, 0.439 mole), which was then added dropwiseto the slurry over 35 minutes. The reaction began to reflux during theaddition with no external heating. After the addition was complete, thereaction was heated to reflux for 20 hours.

The reaction was cooled to room temperature. Methanol (60 mL) was addeddropwise through the dropping funnel over 45 minutes. The reactionbubbled vigorously and began to reflux with no external heating. Sodiumhydroxide (5N, 200 mL) was added. At this point the slurry dissolved togive a cloudy white solution. The reflux condenser was replaced with adistillation head and the solvents which boiled at less than 100° C.were removed by distillation (˜260 mL) and discarded. The distillationhead was replaced with a reflux condenser and the reaction was heated toreflux for three hours, then allowed to cool to room temperature.

The mixture was extracted with ethyl acetate (1×150 mL, then 2×100 mL).The combined organic layers were washed with aqueous saturated NaCl(1×100 mL), dried over magnesium sulfate, filtered and concentrated on arotary evaporator (bath temp. 30° C. and vacuum of ˜5 mm. Hg) to provide26.8 g (99%) of crude title compound as an off white solid.

The above crude title compound was dissolved in boiling ethyl acetate(150 mL). Hexane (150 mL) was added with heating and stirring. Thesolution was allowed to cool with stirring. After 18 hours at roomtemperature, the crystals were filtered, washed with 1:1 ethylacetate:hexane (3×30 mL ), hexane (3×30 mL) and dried to provide 14.6 g(54%) of title compound as a white solid, mp 75°-77° C. A second crop(7.79 g, 29%) and a third crop (1.34 g, 5%) provided additional titlecompound. The total yield of title compound was 23.7 g (88%).

B.[2(S),3aα,4β,7aβ,7aα]-Hexahydro-2-(2-hydroxy-1-phenylethyl)-4,7-epoxy-2H-isoindole-1,3-dione

Into a 2.0 L 3-necked flask was charged(3aα,4β,7β,7aα)-hexahydro-4,7-epoxyisobenzo furan-1,3-dione (Lancaster)(34.1 g, 0.203 mol), Part A (S)-β-aminobenzeneethanol (27.8 g, 0,203mol) and oxalic acid (18.3 g, 0.203 mol). The above mixture wassuspended in THF (500 ml). To the above suspension was addedtriethylamine (Et₃ N) (56 ml) and the resulting mixture was heated toreflux for 8.0 h. The reaction mixture was cooled to room temperatureand poured into sat. NaHCO₃ (300 ml). The resulting mixture wasextracted with ethyl acetate (2×300 ml). The organic extracts werecombined, dried over MgSO₄ and concentrated in vacuo on the rotovap at abath temp. of 35° C. under ˜1.5 mm Hg. The residue was dissolved inethyl acetate (100 ml) at 60 ° C. and hexanes (50 ml) were added. Theresulting solution was allowed to cool to room temperature and put intoa cold room for 14 h. The white solid was filtered using a mediumporosity fritted glass filter and dried in a vacuum oven (˜80mm Hg) for24 h to give title compound (48.7 g, 84%).

C. 2-(2-Bromophenyl)-1,3-dioxolane

A 12 L 3-necked flask fitted with an overhead stirrer was charged with2-bromobenzaldehyde (800 g, 4.324 moles), ethylene glycol (402.6 g,6.485 moles), p-toluenesulfonic acid•H₂ O (3.95 g, 0.021 moles) andtoluene (3.785 kg, 41.074 moles).

One side of the flask was stoppered (glass) and a Dean-Starkseparator/condenser/N₂ port was attached to the other side.

The heterogeneous yellow reaction mixture was stirred under a nitrogenatmosphere and heated to reflux for about 45 minutes.

Water was collected via the Dean-Stark separator and the residue wascooled to room temperature and washed with 1.2 L of saturated aqueousNaHCO₃ followed by 1.2 L of saturated aqueous NaCl.

The combined organic layers were dried over anhydrous MgSO₄, filtered,concentrated on a rotary evaporator and dried under high vacuum toprovide title compound in the form of an oil. The so-formed oil wasvacuum distilled to provide 52 g and 876.2 g of title compound (88.9%yield).

D.[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde

Into an oven-dried, argon purged 500 ml flask, Part C2-(2-bromophenyl)-1,3-dioxolane (71.5 g, 0.313 disclosed in U.S. Pat.No. 5,281,716, which is incorporated herein by reference.

The so-formed oxazole ester IA may then be hydrolyzed employingconventional techniques such as treatment with an aqueous solution of analkali metal base and then aqueous acid to form the corresponding acidIB which may be treated with sodium methoxide, sodium 2-ethylhexanoateor sodium ethoxide to form salt IC in the presence of acetone/methanol.

The term "lower alkyl" or "alkyl" as employed herein includes bothstraight and branched chain radicals of up to 18 carbons, preferably 1to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1, 2 or 3 substituents such as halo, alkenyl, alkynyl, aryl,alkyl-aryl, haloaryl, cycloalkyl, or alkylcycloalkyl.

The term "cycloalkyl" includes saturated cyclic hydrocarbon groupscontaining 3 to 12 carbons, preferably 3 to 8 carbons, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may besubstituted with substituents such as halogen, lower alkyl, and/oralkoxy groups.

The term "aryl" or "Ar" as employed herein refers to monocyclic orbicyclic aromatic groups containing from 6 to 10 carbons in the ringportion, such as phenyl or naphthyl. Aryl (or Ar), phenyl or naphthylmay include substituted aryl, substituted phenyl or substitutednaphthyl, which may include 1 or 2 substituents on either the phenyl ornaphthyl mol) was dissolved in THF (240 ml). Magnesium turnings (11.4 g,0.467 mol) were charged into a separate oven-dried, argon-purged 500 ml3-necked flask equipped with a condenser. To this flask was added aportion (10.0 ml) of the above solution at room temperature. Thereaction initiated by itself after stirring for 5 min. The rest of thesolution was added into the flask at such a rate to maintain a gentlereflux. After all of the solution had been added, the reaction mixturewas stirred for an additional 2.0 h at room temperature to give the arylGrignard reagent bromo[2-(1,3-dioxolan-2-yl)phenyl]magnesium.

The Part B imide (50.0 g, which included 2 g from a previous batch,0.174 mol) was added to an oven-dried, argon purged 3.0 L 3-necked flaskequipped with an addition funnel, dissolved in THF (790 ml), and cooledto -15 ° C. in an ice-methanol bath. To this solution was added C₂ H₅MgCl (87.0 ml of a 2.0M solution in THF) dropwise over a period of 0.5hour via the addition funnel. After the addition was complete, thereaction was stirred for 0.5 hour at -15 ° C. The ice-methanol bath wasremoved and replaced with an ice-water bath. The reaction mixture wasstirred for an additional 0.5 hour at 0° C. To this mixture was addeddropwise over a period of 1.0 hour the above aryl Grignard solution (280ml of a 1.12M solution in THF, 0.313 mol). After the addition wascomplete, the reaction was stirred at 0° C. for 3.0 h. The ice-waterbath was removed and the reaction was stirred for an additional 4.5 h.The reaction mixture was cooled to 0° C. with an ice-water bath andquenched by adding ethanol (1.0 L).

To the resulting mixture was added solid NaBH₄ (15.0 g, 0.397 mol) in 6equal portions over 0.5 hour. The ice-water bath was allowed to melt andthe reaction mixture was allowed to warm to room temperature and stirredfor 14 h. The reaction mixture was poured into 10% Na₂ CO₃ (1.5 L) andthe mixture was extracted with ethyl acetate (3×1.5 L). The organicextracts were combined, washed with brine (1.5 L), dried over MgSO₄,filtered and concentrated in vacuo on the rotary evaporator as describedabove to obtain the crude[1R-[1α,2α(S*),3aα,4α]-3-[[2-(1,3-dioxolan-2-yl)phenyl]hydroxymethyl]-N-(2-hydroxy-1-phenylethyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(104.0 g, 110%) which was used in the next step without any additionalpurification.

The above crude alcohol (104.0 g) was dissolved in toluene (250 ml) andheated to reflux for 3.0 h. The resulting solution was cooled to roomtemperature and then 1N NaOH (750 ml) and ethanol (150 ml) were added.The mixture was vigorously stirred for 4.0 h at room temperature andthen was extracted with ethyl acetate (750 ml). The aqueous layer wasmixed with THF (125 ml). To this mixture was added 10% HCl (350 ml) atroom temperature. The resulting mixture was then stirred at roomtemperature for 14 h during which time a white precipitate formed. Thereaction was cooled to 0 ° C. for 1.0 hour. The white precipitate wasfiltered off using a medium porosity fritted glass filter and washedwith water (100 ml). The solid was dried under high vacuum to give thetitle compound as a white solid (32.0 g, 71%) with 99.9% ee asdetermined by chiral HPLC.

EXAMPLE 2 Alternative Preparation of[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde

A.[2(S),3aα,4β,7⊕,7aα]-Hexahydro-2-[1-(hydroxymethyl)-2-methylpropyl]-4,7-epoxy-2H-isoindole-1,3-dione

A 3 L 3-necked Morton flask, fitted with a condenser and a mechanicalstirrer, was purged with a steady stream of argon for 1 hour. The flaskwas then charged with S-(+)-2-amino-3-methyl-1-butanol (50.0 g, 485mmole) and THF (1000 mL). The resulting mixture was stirred for 5minutes until a homogeneous solution was obtained. Oxalic acid (43.1 g,479 mmole) was added in one portion. Within 5 minutes a thick, whiteprecipitate formed. An additional portion of THF (500 mL) was added tothe flask. (3aα,4β,7β,7aα)-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione(anhydride) (77.0 g, 458 mmole) was added in one portion, followed bytriethylamine (129 mL, 926 mmole). The mixture was heated to reflux for18 hours, then allowed to cool to room temperature. The resulting slurrywas filtered, and the filtrate concentrated on a rotary evaporator to avolume of ˜1 L. The solution was poured into saturated aqueous NaHCO₃ (1L) and extracted with CH₂ Cl₂ (1×1000 mL, then 2×500 mL). The combinedorganic layers were dried over anhydrous MgSO₄, filtered, concentratedon a rotary evaporator, and dried under high vacuum to provide 94.8 g ofcrude title imide.

The above crude imide (94.8 g) was dissolved in hot ethyl acetate (250mL) and diluted with hexane (570 mL) at reflux. The mixture was allowedto cool to room temperature. The resulting crystals were collected bysuction filtration, washed with 2.4: 1 hexane/ethyl acetate (2×100 mL)and hexane (2×100 mL). The material was transferred to a vacuum oven anddried for 2 days under house vacuum (˜80 mm Hg) at ambient temperatureto provide 78.6 g (68%) of title imide. The mother liquor wasconcentrated on a rotary evaporator. A second crop of 9.7 g (8%) wasobtained from ethyl acetate (40 mL) and hexane (120 mL). The total yieldof title alcohol was 88.3 g (76%).

B.[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde

In a flame-dried, argon purged 250 mL 3-necked flask, fitted with acondenser and a dropping funnel, was placed magnesium shot (2.25 g, 92.6mmole) and freshly distilled THF (80 mL). The THF suspension was heatedto reflux and a small crystal of iodine was added to the flask.2-(2-Bromophenyl)-1,3-dioxolane (18.45 g, 80.5 mmole) was added at sucha rate as to maintain vigorous refluxing. Once the addition was complete(˜20 minutes), reflux was maintained with the aid of a heating mantlefor an additional 25 minutes. The mixture was then allowed to cool toroom temperature.

In a flame dried 500 mL flask was added Part A compound (10.00 g, 40.3mmole) and THF (60 mL). The mixture was cooled in a -20° C. bath andethylmagnesium chloride (21.2 mL of a 1.90M solution in THF, 40.3 mmol)was added dropwise to the solution at such a rate so that the internaltemperature did not exceed -10° C. The mixture was then immediatelycooled in a -78° C. bath and the Grignard solution of2-(2-bromophenyl)-1,3-dioxolane (62.7 mL) was added via syringe at sucha rate that the internal temperature did not exceed -65° C. The dry icewas removed from the -78° C. bath and the mixture was allowed to slowlywarm to room temperature with stirring over 5 hours. After stirring atroom temperature for 15 minutes, TLC indicated that no starting materialremained; a new material predominated. The mixture was quenched withabsolute ethanol (145 mL) and sodium borohydride (3.05 g, 80.5 mmole)was added in one portion. The mixture was stirred at room temperaturefor 1 hour. TLC indicated the reduction to be complete. The mixture wascarefully poured into aqueous saturated Na₂ CO₃ (500 mL) and extractedwith CH₂ Cl₂ (2×500 mL). The combined organic layers were dried overMgSO₄, filtered, concentrated on a rotary evaporator, and dried underhigh vacuum at room temperature to provide 18.1 g (112%) of crude[1R-[1α,2α(S*),3aα,4α]-3-[[2-(1,3-dioxolan-2-yl)phenyl]hydroxymethyl]-N-[1-(hydroxymethyl)-2-methylpropyl]-7-oxabicyclo[2.2.1]heptane-2-carboxamidewhich was used in the next step without any additional purification.

The above crude alcohol (18.1 g) was dissolved in toluene (80 mL) andheated to reflux for 1.5 hours. TLC indicated the formation of a newmaterial. The mixture was cooled to room temperature with an ice-bathand diluted with ethanol (20 mL) and 1.0M NaOH (80 mL). The mixture wasstirred at room temperature for 4.5 hours. The layers were separated andthe aqueous layer was washed with CH₂ Cl₂ (2×100 mL). The aqueous layerwas diluted with isopropyl alcohol (20 mL) and then adjusted to pH 1.05with 1.0M HCl (120 mL). The mixture was stirred at room temperature for18 hours, then diluted with THF (180 mL, added in 60 mL increments over7 hours) until the mixture was homogeneous. The solution was stirred atroom temperature overnight, and concentrated on a rotary evaporator toremove volatile organics (160 mL). A white solid formed duringconcentration. The material was filtered and washed with water (3×100mL). The cake was dried in vacuo to provide 6.9 g (66.7% yield) of thetitle aldehyde. Chiral HPLC analysis revealed the material to be a 96:4mixture of enantiomers.

EXAMPLE 3[1S-(1α,2α,3α,4α)]-2-[[2-(3-Methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylicacid (via Scheme 1)

A.[1S-[1α(E),3aα,4β,7β,7aα]]-3-[2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)phenyl]-2-propenoicacid, methyl ester

In a 250 mL flask was placed Example 1 aldehyde (obtained from twodifferent batches) (9.44 g, 36.54 mmole), lithium chloride (1.7 g, 40.19mmole) and acetonitrile (145 mL). The solution was stirred magneticallyunder an argon atmosphere. Trimethylphosphonoacetate (7.32 g, 40.19mmole) was added via syringe followed by1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (6.01 mL, 40.19 mmole). Thesolution became cloudy and the temperature of the reaction rose to 42°C. After 75 minutes, TLC indicated the reaction to be complete. Themixture was poured into aqueous saturated sodium bicarbonate (500 mL)and extracted with methylene chloride (2×500 mL). The combined organiclayers were dried over anhydrous magnesium sulfate, filtered,concentrated on a rotary evaporator (bath temp. 35° C., ˜80 mm Hg) anddried under high vacuum (˜0.5 mm Hg) at room temperature to provide11.36 g (98.9% yield) of the crude title compound as a yellow,crystalline solid.

B.[1S-(1α,2α,3α,4α]-2-[[2-(3-Methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylicacid

The Part A crude vinyl ester (11.36 g) was placed in a 250 mL flask anddissolved in THF (35 mL) and methanol (70 mL). To the magneticallystirred solution was added Pearlman's catalyst (Aldrich) (Pd(OH)₂ /C)(1.14 g). The flask was evacuated, then connected to a balloon filledwith hydrogen. The reaction mixture was stirred at room temperature for2 hours, and then a second portion of Pearlman's catalyst (1.14 g) wasadded. The flask was re-evacuated and reconnected to the balloon filledwith hydrogen. The mixture was stirred at room temperature for anadditional 2 hours. TLC indicated complete conversion to the titlecompound. The balloon was removed and Celite (2.0 g) was added to themixture and stirred for 10 minutes. The mixture was filtered through apad of Celite (45×25 mm). The pad was washed with methanol (50 mL). Thefiltrate was concentrated on a rotary evaporator as described above toprovide a yellow oil. The oil was dissolved in methylene chloride (100mL) and dried over anhydrous magnesium sulfate. The solution wasfiltered, concentrated on a rotary evaporator as described above, anddried under high vacuum (˜0.5 mm Hg) to provide 11.81 g (101.6% yield)of the crude title compound.

The above crude title compound (11.81 g) was dissolved in hot ethylacetate (23 mL) and diluted with hot heptane (46 mL). The mixture wasallowed to cool while being stirred magnetically. The mixture was seededat a temperature of 58° C. with crystals of the title compound. Uponcooling to room temperature, a significant quantity of the titlecompound had crystallized from the solution. An additional portion ofheptane (65 mL) was added and the mixture was stirred for 5 minutes. Themixture was allowed to stand at room temperature overnight. Theresulting solid was collected by suction filtration, washed with heptane(50 mL), then dried under high vacuum at room temperature to provide7.32 g (62.9% yield) of the title compound containing small traces ofyellow material.

The solid and the mother liquor were recombined and dissolved in ethylacetate (120 mL) and treated with Darco KB activated carbon (1.2 g). Themixture was heated to reflux for 2 minutes, then allowed to cool to roomtemperature. Celite (2.4 g) was added, and the mixture was stirred for10 minutes, then filtered through a pad of Celite (45×25 mm). The padwas washed with ethyl acetate (50 mL). The filtrates were concentratedon a rotary evaporator as described above to provide a pale yellow oil.The oil was dissolved in ethyl acetate (23 mL), heated to reflux anddiluted with heptane (46 mL). The mixture was then allowed to cool toroom temperature with stirring. The mixture was seeded with crystals ofthe title compound. After stirring at room temperature for ˜15 minutes,additional heptane (65 mL) was added. The flask was placed in a coldroom (˜4° C.) overnight. The resulting crystals were collected bysuction filtration, washed with heptane (50 mL) and dried under highvacuum (˜0.5 mm Hg) at room temperature to provide 9.97 g (85.7% yield)of the title compound.

EXAMPLE 4[1S-(1α2α,3α,4α)]-2-[[-(3-Methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylicacid (via Scheme 2)

A.[1S-[1α(E),3aα,4β,7β,7aα]]-3-[2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)phenyl]-2-propenoicacid

A dry, argon purged 250 mL one-necked flask was charged with Example 1aldehyde (10 g, 38.8 mmole), malonic acid (18.1 g, 174 mmole) andpyridine (20 mL). The flask was equipped with a reflux condenser and themixture was heated at 85° C. in an oil bath. The solids dissolved afterheating for ten minutes. Piperidine (0.380 mL) was added. The reactionwas stirred at 85° C. for 18 hours and cooled to room temperature. 10%HCl (200 mL) was added over 15 minutes. The solution became thick withthe formation of a precipitate. The slurry was stirred at roomtemperature for three hours. The solid was collected in a mediumscintered glass funnel and washed with water (3×30 mL). A clean 500 mLreceiving flask was attached to the funnel. Acetone (˜240 mL) was addedto dissolve the solid and was then pulled through the funnel. Thefiltrate was concentrated on a rotary evaporator to provide 10.8 g (93%)of the crude title acid as a white solid which was used in the next stepwithout any additional purification.

B.[1S-[1α(E),3aα,4β,7β,7aα]]-3-[2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)phenyl]-2-propenoicacid, methyl ester

The above crude Part A acid (10.7 g, 35.7 mmole) was mixed withmethanol/sulfuric acid (80:1) (360 mL) at room temperature under argonin a 500 mL 2-necked flask equipped with a reflux condenser. The mixturewas heated to 50° C. in an oil bath. As it warmed, the solids dissolved.After six hours, the solution was cooled to room temperature andconcentrated on a rotary evaporator to a slurry (˜50 mL). The slurry wasdiluted with ethyl acetate (100 mL). The solution was washed withaqueous saturated sodium bicarbonate (3×25 mL) and aqueous saturatedNaCl (1×25 mL). The organic layer was dried over magnesium sulfate,filtered and concentrated on a rotary evaporator to provide 10.6 g (95%)of the crude title ester as an off-white, hard solid which was used inthe next step without any additional purification.

C.[1S-(1α,2α,3α,4α)]-2-[[2-(3-Methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylicacid

The above crude Part B ester (10.3 g, 32.8 mmole) was dissolved in asolution of THF (40 mL) and methanol (80 mL) in a 250 mL one-neckedflask equipped with a three-way valve. The valve was connected to aballoon of hydrogen and the house vacuum. The flask was evacuated andfilled with hydrogen three times by turning the valve. Pearlman'scatalyst (1.03 g, 10% by weight) was added. The flask was againevacuated and filled with hydrogen three times. The reaction was stirredat room temperature for two hours.

Celite (15 g) was added to the flask and stirred for 10 minutes. Themixture was filtered through a pad of Celite and concentrated on arotary evaporator. The residue had a grey color. It was dissolved inmethylene chloride (50 mL), dried over magnesium sulfate and filteredthrough another pad of Celite. The filtrate was concentrated on a rotaryevaporator. The product was again dissolved in methylene chloride (25mL) and filtered through a thick pad of Celite to provide a clear,yellow solution. The solvent was removed on a rotary evaporator toprovide 10.4 g (99%) of the crude title acid as a mixture of a whitesolid, a colorless oil and a dark yellow oil.

The crude product was dissolved in boiling ethyl acetate (25 mL). Whileboiling, heptane (50 mL) was added slowly to maintain reflux. The clear,pale yellow solution was then allowed to cool to room temperature withstirring. The mixture was seeded with crystals of the title acid when itreached 50° C., and again when it reached 45° C. The mixture becamecloudy and then thick with solids. After the mixture had reached roomtemperature (˜28° C.), additional heptane (70 mL) was added. The flaskwas placed in a cold room (˜4° C.) over the weekend. The resultingcrystals were collected by suction filtration, washed with heptane (3×50mL) and dried under house vacuum at room temperature for 24 hours toprovide 9.22 g (88%) of the title acid as a fluffy white solid. Theoverall yield from Example 1 aldehyde was 77.8%.

EXAMPLE 5 N-Pentyl-L-Serinamide

A. Carbobenzyloxy-L-serine

L-Serine (20.00 g, 190.3 mmol) was dissolved in water, and aqueoussodium hydroxide was added to adjust the pH of the solution to about 8.5while maintaining the temperature at about 25° C. Benzyl chloroformate(36.0 g, 211.0 mmol) was added while the pH was maintained between 8.3and 8.5 by the addition of aqueous sodium hydroxide and the temperaturewas maintained at about 30° C. The mixture was stirred for about 2hours. The reaction mixture was extracted with methylene chloride. Thephases were separated, and the pH of the aqueous phase was adjusted toabout 7 with concentrated hydrochloric acid. The aqueous phase washeated to about 40° C. under low vacuum to remove any residual methylenechloride. Water was added and the aqueous solution was heated to about60° C. The pH was adjusted to about 2 with concentrated hydrochloricacid while maintaining the temperature at about 60° C. The solution wascooled to about 50° C. while stirring and seed crystals were added. Withstirring, cooling was continued to about 0° C. to complete thecrystallization. The product was collected and the cake was washed withcold (about 5° C.) water. The product was dried under vacuum at about40° C. to afford carbobenzyloxy-L-serine.

B. N-Pentyl-L-serinamide, oxalate (1:1) salt

Under an inert atmosphere, 1,8-diazabicyclo-[5.4.0]undec-7-ene (5.10 g,33.5 mmol) was added to a suspension of Part A carbobenzyloxy-L-serine(7.50 g, 31.4 mmol) in ethanol. Ethyl acetate was added and the mixturewas agitated (optionally, with heating up to about 50° C.) to obtain aclear solution. Pyridine (0.25 g, 3.2 mmol) was added and the mixturewas cooled to about -30° C. Trimethylacetyl chloride (4.12 g, 34.2 mmol)was added and the mixture was maintained at about -30° C. With cooling,n-amylamine (3.00 g, 34.4 mmol) was added and the mixture was stirred atabout -10° C. for about 2 hours. Cooling was discontinued and aqueousphosphoric acid was added. The mixture was warmed to about 10° C. andthe phases were separated. The organic solution was washed sequentiallywith aqueous phosphoric acid, aqueous potassium carbonate, and brine.Throughout these extractions, the aqueous phase was back extracted withethyl acetate. The combined organic solution was distilled under vacuumat about 25° C. while ethanol was added until all of the ethyl acetatewas removed. Under an inert atmosphere, 10% palladium on carbon (50%water, 0.75 g) was added. The resulting mixture was purged with nitrogenand then stirred in the presence of hydrogen at about 25° C. for about 6hours. The catalyst was removed by filtration, and the clear filtratewas partially concentrated under vacuum at about 30° C. The concentratedfiltrate was added to a solution of oxalic acid dihydrate (4.35 g, 34.5mmol) in ethanol and water and a thick precipitate was formed. Thesuspension was heated to reflux to obtain a clear solution. Water wasadded at the reflux temperature until a slight turbidity was observed.The mixture was cooled to about 0° C. and stirred until crystallizationwas complete (about 1 hour). The product was collected and the cake waswashed with ethanol. The product was dried under vacuum at about 25° C.to afford the title compound.

EXAMPLE 6[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, monosodium salt

A.[1S-[1α,2α,3α(R*),4α]]-2-[[3-[[[1-(Hydroxymethyl)-2-oxo-2-(pentylamino)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

Under an inert atmosphere, a catalytic amount of dimethylformamide(0.067 mL, 0.87 mmol) was added to a solution of Example 3 carboxylicacid (6.66 g, 20.9 mmol) in toluene and the resulting mixture was cooledto about 0° C. While maintaining the temperature below 0° C., oxalylchloride (2.96 g, 23.3 mmol) was added and the mixture was stirred atabout 5° C. for about 3 hours. The resulting acid chloride solution waspartially concentrated under vacuum at about 40° C. and then used in thecoupling reaction described below.

Meanwhile, Example 5 amide (6.17 g, 23.3 mmol) was added to a solutionof sodium bicarbonate (9.63 g, 115 mmol) in water while the temperaturewas maintained at about 20° C. Methyl ethyl ketone was added and thebiphasic mixture was cooled to about 0° C. While maintaining thetemperature at about 0° C., the previously prepared acid chloridesolution was added with stirring. The mixture was stirred at about 5° C.for about 20 hours and then heated to about 60° C. and the phases wereallowed to separate. The organic phase was washed at about 50° C.sequentially with saturated sodium bicarbonate solution, aqueousphosphoric acid, and brine. The organic solution was partiallyconcentrated under vacuum at about 40° C. to obtain a thick suspension.n-Heptane was added and the resulting mixture was cooled to about 20° C.with stirring. The product was collected and the cake was washed withn-heptane. The product was dried under vacuum at about 35° C. to affordthe title ester.

B.[1S-[1α,2α,3α(R*),4α]]-2-[[3-[4,5-Dihydro-4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

Under an inert atmosphere, Part A ester (7.00 g, 14.7 mmol) wasdissolved in dry dimethylformamide. The moisture content of theresulting solution must be <0.1% w/w; if it was higher, the solution wasfirst dried by vacuum distillation of a portion of the solvent and drydimethylformamide was added to restore the original solution volume.Triethylamine (4.29 g, 42.4 mmol, plus approximately 1 mmol per mmol ofwater measured in the Part A ester solution) was added and the mixturewas cooled to about 0° C. While maintaining the temperature below 5° C.,methanesulfonyl chloride (2.02 g, 17.6 mmol, plus approximately 0.4 mmolper mmol of water measured in the Part A ester solution) was added. Thereaction mixture was stirred at about 5° C. for about 5 hours. Themixture was warmed to about 25° C. and stirred for about 20 hours. Cold(about 5° C.) water was added while maintaining the pH at about 8.0 bythe addition of aqueous phosphoric acid. The resulting suspension wasstirred at about 10° C. for about 1 hour. The product was collected andthe cake was washed with cold (about 5° C.) water. The product was driedunder vacuum at about 25° C. to afford the title compound.

C.[1S-(1α,2α,3,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

Under an inert atmosphere, hexamethylenetetramine (5.89 g, 42.0 mmol)was added to a mixture of copper(II) bromide (8.63 g, 38.6 mmol) andmethylene chloride. A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene(6.38 g, 41.9 mmol) in methylene chloride was added with slight coolingto maintain the temperature at about 30° C. A solution of Part B ester(4.50 g, 9.86 mmol) in methylene chloride was added, and the reactionmixture was stirred at about 30° C. for about 14 hours. The mixture wascooled to about 20° C. and filtered, and the cake was washed withmethylene chloride. At this point, the filtrate may be combined with thefiltrate from another run. The filtrate was concentrated under vacuum atabout 30° C., and ethyl acetate, water and aqueous ammonia were added tothe resulting residue. The phases were separated, and the organic phasewas washed with a mixture of water and aqueous ammonia. The resultingaqueous solution was back extracted with ethyl acetate. The combinedorganic phase was washed sequentially with aqueous phosphoric acid andbrine. Brine was added to the organic phase and the pH was adjusted toabout 7 with saturated sodium bicarbonate. The organic solution wasseparated and partially concentrated under vacuum at about 40° C. Seedcrystals of the title compound were added followed by n-heptane. Theremaining ethyl acetate was replaced with n-heptane by avacuum-distillation exchange procedure at a temperature of 40° C. orbelow. The product was collected and the cake was washed with n-heptane.The product was dried under vacuum at about 25° C. to afford the titlecompound.

D.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, monosodium salt

Under an inert atmosphere, 1N sodium hydroxide (3.6 mL, 3.6 mmol) wasadded to a cold (about 5° C.) solution of Part C ester (0.600 g, 1.32mmol) in tetrahydrofuran. The reaction mixture was stirred at about 25°C. for about 4 hours. The reaction mixture was partially concentratedunder vacuum at about 35° C. The concentrated solution was diluted withwater and then washed with diethyl ether. The phases were separated andthe pH of the aqueous solution was adjusted to about 7 with concentratedhydrochloric acid. Methylene chloride was added and acidification wascontinued with stirring to a pH of about 2. The phases were separatedand the aqueous layer was extracted with methylene chloride. Theresulting combined organic extract was washed sequentially with waterand brine. The organic solution was dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum at about 25° C. to asolid. The resulting solid was dissolved in hot (about 90° C.)acetonitrile, and the solution was allowed to stand at room temperaturewithout stirring for about 12 hours. The product was collected and thecake was washed with cold (about 5° C.) acetonitrile. The product wasdried under vacuum at about 35° C. to afford the title compound.

under an inert atmosphere, the title compound (461 g, 1.04 mol) wasdissolved in acetone at about 50° C. The resulting solution was cooledto about 35° C. and a solution of 25% w/w sodium methoxide in methanol(0.264 mL, 1.15 mol) was added. The resultant slurry was allowed to coolto about 25° C. with stirring. The product was collected and the cakewas washed with acetone. The product was dried under vacuum at about 35°C. to afford the title compound.

EXAMPLE 7[2S-(2α,3aα,4β,7β,7aα]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl]benzaldehyde

A.[2(S),3α,4β,7β,7α]-Octahydro-2-(2-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione

An argon purged 500 mL one-necked flask was charged with(3aα,4β,7β,7aα)-hexahydro-4,7-epoxyisobenzofuran-1,3-dione (10.0 g, 59.5mmole) and toluene (225 mL). The slurry was difficult to stir with amagnetic stir bar. (S)-(-)-α-Methylbenzylamine (Aldrich) (8.1 mL, 62.8mmole) was added. The flask was equipped with a reflux condenser and aDean-Stark trap. The mixture was heated at reflux under argon for 3.5hours and then was cooled to room temperature. The mixture wasconcentrated on a rotary evaporator to provide 16.52 g (100%) of crudetitle imide as a white crumbly solid.

The crude title imide was dissolved in boiling ethyl acetate (30 mL) togive a cloudy mixture. The solution was filtered to give 86 mg of awhite solid and a clear, pale yellow filtrate. The filtrate wasconcentrated on a rotary evaporator to a white solid. It was dissolvedin boiling ethyl acetate (22 mL). Hexane (56 mL) was added until thesolution just became cloudy. The solution was cooled to room temperaturewithout stirring and then was stored in the cold room (˜4° C.)overnight. The crystals were filtered and washed with hexane:ethylacetate (2.5:1, 3×30 mL) and hexane (3×50 mL) and were dried under housevacuum at room temperature to provide 13.44 g (83%) of a white solid.

The crystals and mother liquor were recombined and dissolved in ethylacetate (˜200 mL) to give a cloudy white solution. The organic solutionwas washed with 1N HCl (2×50 mL), saturated aqueous sodium bicarbonate(1×50 mL) and saturated sodium chloride (1×50 mL). The organic layer wasdried over magnesium sulfate, filtered and the solvent removed on arotary evaporator to provide 14.541 g (90%) of crude title imide as anoff-white crumbly solid.

The solid was dissolved in boiling ethyl acetate (19 mL). With stirringand heating, hexane (100 mL) was added until white crystals abruptlybegan falling out of the solution. The solution was cooled to roomtemperature without stirring. The mixture was stored in the cold room(˜4° C.) for 18 hours. The resulting crystals were filtered, washed withhexane (3×30 mL) and dried under house vacuum at room temperature toprovide 13.59 g (84%) of the title imide as shiny white crystals. Asecond crop (712 mg, 4%) provided additional title imide. The totalyield of title imide was 14.302 g (88%).

B.[1R-[1α,2α(S*),3aα,4α]-3-[[2-(1,3-Dioxolan-2-yl)phenyl]hydroxymethyl]-N-(1-phenylethyl)-2-methylpropyl]-7-oxabicyclo[2.2.1]heptane-2-carboxamide

In an oven-dried, argon purged 100 ml flask,2-(2-bromophenyl)-1,3-dioxolane (16.8 g, 0.0737 mol) was dissolved inTHF (30.0 ml). Magnesium turnings (2.1 g, 0.0875 mol) were charged intoa separate oven-dried, argon-purged 100 ml 3-necked flask equipped witha condenser. To the magnesium turnings was added a portion (5.0 ml) ofthe above solution of 2-(2-bromophenyl)-1,3-dioxolane at roomtemperature. The reaction initiated by itself after stirring for 5 min.The rest of the solution of 2-(2-bromophenyl)-1,3-dioxolane was addedinto the flask at such a rate which maintained a gentle reflux over aperiod of 40 min. After all of the solution had been added, the reactionmixture was stirred for another 1.0 hour at room temperature to give thearyl Grignard.

The Part A imide (10.0 g, 0.0369 mol) was added to an oven-dried, argonpurged 250 ml 3-necked flask equipped with an addition funnel and amechanical stirrer. The imide was suspended in THF (14 ml), and cooledin an ice-water bath to 0° C. The Grignard solution of2-(2-bromophenyl)-1,3-dioxolane prepared above (38.0 ml of a 1.94Msolution in THF, 0.0737 mol) was added dropwise over a period of 40 minto this mixture. After the addition was complete, the reaction wasstirred at 0° C. for 1.0 h. The ice-water bath was removed and thereaction was stirred for an additional 3.0 h at room temperature.

The reaction mixture was cooled to 0° C. with an ice-water bath andquenched by adding ethanol (100 ml). To the resulting mixture was addedsolid NaBH₄ (3.3 g, 0.0873 mol) in 6 equal portions over 20 min. Theice-water bath was allowed to melt and the reaction mixture was allowedto warm to room temperature and stirred for 17 h. The reaction mixturewas poured into 10% Na₂ CO₃ (400 ml) and the mixture was extracted withethyl acetate (3×300 ml). The organic extracts were combined, washedwith brine (300 ml), dried over MgSO₄, filtered and concentrated invacuo using a rotary evaporator to obtain the crude title alcohol (22.3g, 106%) which was used in the next step without any additionalpurification.

C.[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxy-isobenzofuran-1-yl)benzaldehyde

The Part B crude alcohol (22.3 g) was dissolved in toluene (50 ml) andheated to reflux for 3.0 h. The resulting solution was cooled to roomtemperature and then 1N NaOH (150 ml) and ethanol (38 ml) were added.The mixture was vigorously stirred for 4.0 h at room temperature andthen was extracted with ethyl acetate (130 ml). The aqueous layer wasmixed with THF (26 ml). To this mixture was added 10% HCl (70 ml) atroom temperature. The resulting mixture was then stirred at roomtemperature for 14 h during which time a white precipitate formed. Thereaction was cooled to 0° C. for 1.0 hour. The white precipitate wasfiltered off using a medium fritted glass filter and washed with water(20 ml). The solid was dried under high vacuum to give the titlealdehyde as a white solid (7.7 g, 81%) with >99.9% ee as determined bychiral HPLC.

EXAMPLE 8[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

A.[2(1S,2R),3aα,4β,7β,7aα]-Hexahydro-2-(2-hydroxy-1-methyl-2-phenylethyl)-4,7-epoxy-2H-isoindole-1,3-dione

A solution of (1S,2R)-(+)-norephedrine (9 g, 59.5 mmole) intetrahydrofuran (THF) (150 mL) was stirred under argon at roomtemperature. Oxalic acid (5.4 g, 60.0 mmole) was added as a solid,followed by THF (50 mL). The mixture became thick with a whiteprecipitate and stopped stirring.(3aα,4β,7β,7aα)-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (Lancaster,10 g, 59.5 mmole) was added as a solid. Triethylamine (17 mL, 122 mmole)was added. The mixture was heated to reflux at which point it beganstirring again. The reaction was heated at reflux for 24 hours.

After cooling to room temperature, the reaction mixture was transferredto a separatory funnel containing saturated sodium bicarbonate (200 mL)and methylene chloride (400 mL). The layers were separated. The aqueouslayer was extracted with methylene chloride (1×200 mL). Saturated sodiumbicarbonate (100 mL) was added to the aqueous layer. The aqueous layerwas extracted with methylene chloride (1×200 mL). The combined organiclayers were dried over magnesium sulfate, then filtered and concentratedin vacuo to provide 17.6 g (98%) of the title imide as a yellow oil.

The crude imide was crystallized from hot ethyl acetate/hexane. Thestirring was stopped and the mixture was cooled to room temperature andstored in the cold room for three days. The solid was filtered, washedwith hexane (3×) and dried in vacuo to produce 14.1 g (79%) of the titleimide as an off-white solid.

Analytical Data

TLC: Ethyl acetate:hexane 8:2; R_(f) =0.74; visualization:phosphomolybdic acid ¹ H and ¹³ C NMR: Consistant. Rotation: [α]_(D)=-40.1° (c=5.32, CH₃ OH) m.p.: 122°-124° C. Microanalysis: Cal'd for C₁₇H₁₉ N₁ O₄ •0.07 mole H₂ O: C, 67.46; H, 6.38; N, 4.63. Found: C, 67.64;H, 6.37; N, 4.66.

B.[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

To a solution of Part A imide (604 mg, 2.01 mmol) in tetrahydrofuran(9.0 ml) was added EtMgCl (1.0 ml of a 2.0M solution in tetrahydrofuran,2.0 mmol) at -78° C. dropwise via a syringe. After the addition wascompleted, the reaction was stirred for 0.5 hour at -78° C. To thismixture was added dropwise the Grignard solution of2-(2-bromophenyl)-1,3-dioxolane (2.84 ml of a 1.41M solution intetrahydrofuran, 4.0 mmol) at -78° C. After the addition was completed,the reaction was stirred at -78° C. for 4.0 h. The dry ice bath wasremoved and the reaction was stirred for an additional 2.0 h. Thereaction mixture was cooled to 0° C. with an ice-water bath and quenchedby adding ethanol (15 ml). To the resulting mixture was added solidNaBH₄ (300 mg, 7.9 mmol). The ice-water bath was allowed to melt and thereaction mixture was allowed to warm to room temperature and stirred for14 h. The reaction mixture was poured into 10% Na₂ CO₃ (20 ml) and themixture was extracted with ethyl acetate (3×50 ml). The organic extractswere combined, dried over MgSO₄, filtered and concentrated in vacuo toobtain the crude benzylic alcohol (1.22 g, 104%) which was used in thenext step without any additional purification.

The above crude benzylic alcohol (1.22 g) was dissolved in toluene (20ml) and heated to reflux for 3.0 h. The resulting solution was cooled toroom temperature and then concentrated in vacuo to give the crudelactone acetal. Purification of the crude product on flash silica gel(1×10 cm, hexane first followed by 20% ethyl acetate/hexane as eluant)gave the title lactone acetal as a colorless oil which solidified uponstanding at room temperature (553 mg, 91%) with 96% ee as determined bychiral HPLC.

The title lactone acetal is then treated with base such as NaOH in thepresence of an alcohol solvent such as ethanol to form a salt which istreated with strong acid such as HCl to form the aldehyde intermediateas described in Example 1.

EXAMPLE 9[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

A.[2(R),3aα,4β,7β,7aα]-Octahydro-1,3-dioxo-N-pentyl-.alpha.-(hydroxymethyl)-4,7-epoxy-2H-isoindole-2-acetamide

In an argon purged 1 L 3-necked flask, fitted with a reflux condenser,was placed 28.0 g of(3aα,4β,7β,7aα)-hexahydro-4,7-epoxyisobenzofuran-1,3-dione, 45 g ofExample 5 amine and 575 mL of tetrahydrofuran (THF). To the stirredsuspension was added 50 mL of triethylamine. The mixture was heated toreflux for 6 hours. The mixture was then allowed to cool to roomtemperature. The mixture was poured into saturated sodium bicarbonate (2L) and extracted with methylene chloride (3×1 L, 500 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo to provide the crude title imide.

The crude title imide was dissolved in 300 mL of hot ethyl acetate.Hexane (520 mL) was added slowly, while maintaining reflux. Afteraddition of the hexane was complete, heating was discontinued and themixture was allowed to cool to room temperature. The resulting crystalswere collected by suction filtration to provide 41.4 g (77%) of thetitle imide. A second crop was obtained from the mother liquor toprovide an additional 7.33 g (14%) of the title imide.

Analytical Data

TLC; Ethyl actate: hexane 7:3, R_(f) =0.13; visualization:phosphomolybdic acid. Microanalysis: Cal'd for C₁₆ H₂₄ N₂ O₅ : C, 59.24;H, 7.46; N, 8.64. Found: C, 59.34; H, 7.56; N, 8.72

B.[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

To a solution of Part A imide (602 mg, 2.00 mmol) in tetrahydrofuran(8.0 ml) was added EtMgCl (2.0 ml of 2.0M solution in tetrahydrofuran,4.0 mmol) at 0° C. dropwise via a syringe. After the addition wascompleted, the reaction was stirred for 0.5 hour at room temperature.The mixture was cooled to 0° C. and to this mixture was added dropwisethe Grignard solution of 2-(2-bromophenyl)-1,3-dioxolane (2.7 ml of a1.096M solution in tetrahydrofuran, 2.96 mmol). After the addition wascompleted, the reaction was stirred at 0° C. for 1.0 h. The reaction wasquenched by adding ethanol (8 ml). To the resulting mixture was addedsolid NaBH₄ (400 mg, 10.5 mmol). The reaction mixture was stirred for 2h at room temperature. The reaction mixture was poured into 10% Na₂ CO₃(30 ml) and the mixture was extracted with ethyl acetate (2×40 ml). Theorganic extracts were combined, dried over MgSO₄, filtered andconcentrated in vacuo to obtain the crude benzylic alcohol which wasused in the next step without any additional purification.

The above crude benzylic alcohol was dissolved in toluene (20 ml) andheated to reflux for 3.0 h. The resulting solution was cooled to roomtemperature and then concentrated in vacuo to give the crude lactoneacetal. Purification of the crude product on flash silica gel (1×10 cm,hexane first followed by 20% ethyl acetate/hexane as eluant) gave thepure lactone acetal as a colorless oil which solidified upon standing atroom temperature (324 mg, 53%) with 61.6% ee as determined by chiralHPLC.

The title lactone acetal may be employed to form the Example 1 aldehydeemploying procedures described in Example 1.

EXAMPLE 10[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

A.[2(R),3aα,4β,7β,7aα]-Octahydro-1,3-dioxo-N-pentyl-.alpha.-[[(tributylsilyl)oxy]methyl]-4,7-epoxy-2H-isoindole-2-acetamide

In a 500 mL flask was placed 10.0 g of the Example 9, Part A imide, 250mL of dimethylformamide (DMF, anhydrous), 2.31 g of imidazole and 5.11 gof tert-butyldimethylsilyl chloride (TBS-Cl). The mixture was stirred atroom temperature for 17 hours, then diluted with diethyl ether (500 mL)and washed with sat'd sodium bicarbonate (300 mL), water (4×400 mL) andbrine (300 mL). The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo to provide 12.3 g (91%) of the titleTBS-protected imide.

Analytical Data

TLC: Ethyl acetate:hexanes 3:2; R_(f) =0.6; visualization:phophomolybdic acid.

B.[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)-phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

To a solution of the Part A imide (410 mg, 1.0 mmol) in tetrahydrofuran(2.0 ml) was added EtMgCl (0.5 ml of 2.0M solution in tetrahydrofuran,1.0 mmol) at 0° C. dropwise via a syringe. After the addition wascompleted, the reaction was stirred for 0.5 hour at 0° C. To thismixture was added dropwise the Grignard solution of2-(2-bromophenyl)-1,3-dioxolane (1.7 ml of a 1.2M solution in 50%tetrahydrofuran/toluene, 2.04 mmol). After the addition was completed,the reaction was stirred at 0° C. for 1.0 h. The reaction mixture wasstirred for an additional 2.0 h at room temperature. The reactionmixture was cooled to 0° C. and additional Grignard solution of2-(2-bromophenyl)-1,3-dioxolane (1.5 ml of a 0.73M solution intetrahydrofuran, 1.10 mmol) was added. The reaction mixture was stirredfor 10 min at 0° C. and then for 1.0 h at room temperature. The reactionwas quenched by adding ethanol (8 ml). To the resulting mixture wasadded solid NaBH₄ (200 mg, 5.2 mmol). The reaction mixture was stirredfor 14 h at room temperature. The reaction mixture was poured into 10%Na₂ CO₃ (15 ml) and the mixture was extracted with ethyl acetate (2×20ml). The organic extracts were combined, dried over MgSO₄, filtered andconcentrated in vacuo to obtain the crude benzylic alcohol which wasused in the next step without any additional purification.

The above crude benzylic alcohol was dissolved in toluene (10 ml) andheated to reflux for 3.0 h. The resulting solution was cooled to roomtemperature and then concentrated in vacuo to give the crude titlelactone acetal. Purification of the crude product on flash silica-gel(1×10 cm, 15% ethyl acetate/hexane as eluant) gave the title lactoneacetal as a colorless oil which solidifies upon standing at roomtemperature (110 mg, 35%) with 86% ee as determined by chiral HPLC.

The title lactone acetal may be employed to form the Example 1 aldehydeemploying procedures described herein.

EXAMPLE 11 [2(1S,2R),3aα,4β,7β,7aα]-Hexahydro-2-(2-hydroxy-1,2-diphenylethyl)-4,7-epoxy-2H-isoindole-1,3-dione

A solution of (1R,2S)-(-)-2-Amino-1,2-diphenylethanol (6.3 g, 29.5mmole) in tetrahydrofuran (THF) (75 mL) was stirred under argon at roomtemperature. Oxalic acid (2.7 g, 30.0 mmole) was added as a solid,followed by THF (25 mL). The mixture became thick with white precipitateand stopped stirring.(3aα,4β,7β,7aα)-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (Lancaster, 5g, 29.7 mmole) was added as a solid. Triethylamine (8.3 mL, 59.5 mmole)was added. The mixture was heated to reflux at which point it beganstirring again. The reaction refluxed for 22 hours.

After cooling to room temperature, the reaction mixture was transferredto a separatory funnel containing saturated sodium bicarbonate (100 mL)and methylene chloride (200 mL). The layers were separated. The aqueouslayer was extracted with methylene chloride (2×200 mL). The combinedorganic layers were dried over magnesium sulfate, then filtered andconcentrated in vacuo to provide 12.4 g (116%) of the title compound asa pale yellow foam.

The crude title compound was crystallized from hot ethyl acetate/hexane.The stirring was stopped and the mixture was cooled to room temperature,and stored in the cold room overnight. The solid was filtered, washedwith hexane (3 times) and dried in vacuo to produce 8.14 g (76%) of thetitle compound as a white solid.

Analytical Data

TLC: Ethyl acetate:hexane 8:2; R_(f) =0.81.; visualization:phosphomolybdic acid Rotation: [α]_(D) =+43.7° (c=2.59, CH₃ OH) m.p.:174°-176° C.

Following the procedure of Example 1, Parts B and C, the title imide maybe employed to form the Example 1 aldehyde intermediate.

EXAMPLE 12[2(S),3aα,4β,7β,7aα]-Hexahydro-2-[1-(hydroxymethyl)-2-methylpropyl]-4,7-epoxy-2H-isoindole-1,3-dione

A solution of (S)-(+)-2-amino-3-methyl-1-butanol (6.2 g, 60.1 mmole) inTHF (150 mL) was stirred under argon at room temperature. Oxalic acid(5.36 g, 60.0 mmole) was added as a solid, followed by tetrahydrofuran(THF) (50 mL). The mixture became thick with white precipitate andstopped stirring.(3aα,4β,7β,7aα]-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (Lancaster,10 g, 59.5 mmole) was added as a solid. Triethylamine (17 mL, 122 mmole)was added. The mixture was heated to reflux at which point it beganstirring again. The reaction refluxed for 23 hours.

After cooling to room temperature, the reaction mixture was transferredto a separatory funnel containing saturated sodium bicarbonate (300 mL)and methylene chloride (600 mL). The layers were separated. The aqueouslayer was extracted with methylene chloride (1×300 mL and 1×200 mL). Thecombined organic layers were dried over magnesium sulfate, then filteredand concentrated in vacuo to provide 9.8 g (65%) of the title compoundas a pale yellow solid.

The crude title compound was taken up in hot ethyl acetate (10 mL).Hexane (6 mL) was added with stirring until solids abruptly began tocome out. The stirring was stopped. The mixture was cooled to roomtemperature and stored in the cold room for 16 hours. The solid wasfiltered, washed-with hexane (3×) and dried in vacuo to produce 5.8 g(39%) of the title compound as a pale yellow solid. A second cropafforded 2.97 g (20%) of the title compound as a white solid.

Analytical Data

TLC: Ethyl acetate:hexane 8:2; R_(f) =0.46; visualization:phosphomolybdic acid Rotation: [α]_(D) =+6.30° (c=5.05, CH₃ OH) m.p.:102°-103° C.

Microanalysis: Cal'd for C₁₃ H₁₉ N₁ O₄ •0.10 mole EtOAc: C, 61.36; H,7.62; N, 5.34. Found: C, 61.46; H, 7.57; N, 4.97. K.F. Found: 0.09.

The title imide may be employed to form the Example 1 benzaldehyde usingprocedures described herein.

EXAMPLE 13[2(S),3aα,4β,7β,7aα]-Hexahydro-2-[1-(hydroxymethyl)-2-phenylethyl]-4,7-epoxy-2H-isoindole-1,3-dione

A solution of (S)-(-)-2-amino-3-phenyl-1-propanol (9 g, 59.5 mmole) intetrahydrofuran (THF) (150 mL) was stirred under argon at roomtemperature. Oxalic acid (5.36 g, 59.5 mmole) was added as a solid,followed by THF (50 mL). The mixture became thick with white precipitateand stopped stirring.(3aα,4β,7β,7aα]-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (Lancaster,10 g, 59.5 mmole) was added as a solid. Triethylamine (17 mL, 122 mmole)was added. The mixture was heated to reflux at which point it beganstirring again. The reaction refluxed for 22 hours.

After cooling to room temperature, the reaction mixture was transferredto a separatory funnel containing saturated sodium bicarbonate (200 mL)and methylene chloride (400 mL). The layers were separated. Saturatedsodium bicarbonate (100 mL) and methylene chloride (100 mL) were addedto the aqueous layer. The contents of the separatory funnel werefiltered through a coarse glass frit. A cake of white solid wascollected on the frit and discarded The filtrate was separated withoutproblem. The aqueous layer was extracted with methylene chloride (1×100mL). The combined organic layers were dried over magnesium sulfate, thenfiltered and concentrated in vacuo to provide 12.3 g (68%) of the titlecompound as a yellow solid.

The crude title compound was taken up in hot ethyl acetate (250 mL) andthen cooled. The resulting solid was filtered off. The filtrate wasconcentrated, then dissolved in hot ethyl acetate (45 mL). Hexane (90mL) was added with stirring until the solution turned cloudy. Thestirring was stopped and the mixture was cooled to room temperature. Thesolid was filtered, washed with hexane (3×30 mL) and dried in vacuo toproduce 9.89 g (55%) of the title compound as a pale yellow solid.

Analytical Data

TLC: Ethyl acetate:hexane 8:2; R_(f) =0.41; visualization:phosphomolybdic acid Rotation: [α]_(D) =67.8° (c=5.70, CH₃ OH) m.p.:129°-131° C.

Microanalysis: Cal'd for C₁₇ H₁₉ N₁ O₄ : C, 67.76; H, 6.35; N, 4.65.Found: C, 67.72; H, 6.32; N, 4.66. K.F. Found: 0.00

The title imide may be employed to form the Example 1 aldehyde usingprocedures described herein.

EXAMPLE 14[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

A.[2(S),3aα,4β,7β,7aα]-Hexahydro-2-(2-hydroxy-1-phenylethyl)-4,7-epoxy-2H-isoindole-1,3-dione

A solution of (R)-(-)-2-phenylglycinol (4 g, 29.2 mmole) intetrahydrofuran (THF) (75 mL) was stirred under argon at roomtemperature. Oxalic acid (2.6 g, 28.9 mmole) was added as a solid,followed by THF (25 mL). The mixture became thick with white precipitateand stopped stirring.(3aα,4β,7β,7aα]-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione (Lancaster,4.9 g, 29.1 mmole) was added as a solid. Triethylamine (8 mL, 57.4mmole) was added. The mixture was heated to reflux at which point itbegan stirring again. The reaction was refluxed for 18 hours.

After cooling to room temperature, the reaction mixture was transferredto a separatory funnel containing saturated sodium bicarbonate (100 mL)and methylene chloride (200 mL). The layers were separated. Saturatedsodium bicarbonate (100 mL) and methylene chloride (100 mL) were addedto the aqueous layer and separated with difficulty. The aqueous layerwas extracted with methylene chloride (1×100 mL) with difficulty. Thecombined organic layers were dried over magnesium sulfate, then filteredand concentrated in vacuo to provide 8.54 g (100%) of the title imide asa yellow foam.

The crude title imide was dissolved in EtOAc (45 mL) and heated toreflux. Hexane (45 mL) was added with stirring until the solution justturned cloudy. The stirring was stopped and the mixture was cooled toroom temperature. The solid was filtered, washed with 3:1 hexane:ethylacetate (3×30 mL) and dried in vacuo to produce 6.42 g (77%) of thetitle imide as a pale yellow solid.

Analytical Data

TLC: Ethyl acetate:hexane 8:2; R_(f) =0.39; visualization:phosphomolybdic acid Rotation: [α]_(D) =-0.409° (c=6.60, CH₃ OH) m.p.:121°-123° C.

Microanalysis: Cal'd for C₁₆ H₁₇ N₁ O₄ : C, 66.89; H, 5.96; N, 4.88.Found: C, 66.7; H, 5.94; N, 4.97

B.[3R-(3α,3aα,4β,7β,7aα)]-3-[2-(1,3-Dioxolan-2-yl)phenyl]hexahydro-4,7-epoxy-1(3H)-isobenzofuranone

In a 25 mL flame-dried, 2-necked flask, fitted with a reflux condenser,was placed 0.0802 g of magnesium metal and 11.5 mL of tetrahydrofuranand a crystal of I₂. To the warmed solution was added 0.6545 g of2-(2-bromophenyl)-1,3-dioxolane. The mixture was heated to reflux and asecond crystal of I₂ and 20 μL of 1,2-dibromoethane were added. Grignardformation commenced immediately. After 40 minutes at reflux, theformation of the Grignard reagent appeared to be complete. The solutionwas allowed to cool to room temperature.

In a separate, flame-dried 25 mL flask was placed 0.2946 g of the Part Aimide, and 3.0 mL of tetrahydrofuran. The mixture was cooled in a -78°C. bath and the Grignard reagent prepared above was added via syringe atsuch a rate that the internal temperature never rose above -70° C. Afterthe addition was complete, the mixture was allowed to warm to roomtemperature over 5 hours. The mixture was poured into saturated sodiumbicarbonate (60 mL) and extracted with methylene chloride (2×60 mL). Thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo to provide 0.5950 g of crude addition product,which was carried on without purification.

The crude product was placed in a 25 mL flask with 2 mL oftetrahydrofuran and 2 mL of ethanol. To the stirred solution was added0.0789 g of sodium borohydride. The mixture was stirred at roomtemperature for 1 hour, then poured into saturated sodium bicarbonate(60 mL) and extracted with methylene chloride (2×60 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated in vacuo to provide 0.6 g of crude benzylic alcohol, whichwas carried on without purification.

The crude benzylic alcohol was placed in a 25 mL flask with 10.5 mL oftoluene. The flask was fitted with a reflux condenser and the mixturewas heated to reflux for 5 hours, then at 100° C. for 18 hours. Themixture was allowed to cool to room temperature, then loaded directlyonto a silica gel column (30×230 mm) and eluted with 2:3 ethylacetate:hexanes (1 L) followed by 3:2 ethyl acetate:hexanes (1 L) toprovide 0.17 g (63%) of the desired title lactone-acetal.

Analytical Data

TLC: Ethyl acetate:hexane 2:3; R_(f) =0.55; visualization:p-Anisaldehyde stain. Rotation: [α]_(D) =+40.2° (c=0.56, CH₃ OH)

The title lactone acetal may be employed to form the Example 1 aldehydeemploying procedures described herein.

The following Table A shows the ratio of desired to undesiredenantiomers of the lactone acetal obtained from various imides and theGrignard reagant prepared from 2-(2-bromophenyl)-1,3-dioxolane or thearyl lithium reagent prepared from 2-(2-bromophenyl)-1,3-dioxolane.

                  TABLE A                                                         ______________________________________                                        Selection of an Aryl Nucleophile/Imide Combination.                           ______________________________________                                         ##STR38##                                                                     ##STR39##                                                                     ##STR40##                                                                    Ex.  R*           ArM              Ratio of                                   No.  (config)     (eg)      % Yield                                                                              Enantiomers.sup.1                          ______________________________________                                        15   Norephedrine ArMgBr    41%    28:72                                           (1S, 2R)     (2.51)                                                      16   Norephedrine ArLi      59%    38:62                                           (1S, 2R)     (2.51)                                                      17   Phenylglycinol                                                                             ArMgBr    63%    13:87                                           (R)          (2.78)                                                      18   Phenylglycinol                                                                             ArLi      29%    25:75                                           (R)          (2.52)                                                      19   Valinol      ArMgBr    65%    86:14                                           (S)          (2.77)                                                      ______________________________________                                         .sup.1 Ratios are expressed as the ratio of desired to undesired              LactoneAcetal.                                                           

Wittig-Horner Olefination was studied as a means to convert the aldehydeof Example 1 to Unsaturated Ester (Example 3A). The results of thisstudy are shown in Table B below.

                                      TABLE B                                     __________________________________________________________________________    Wittig-Horner Olefination of Example 1 aldehyde.                              __________________________________________________________________________     ##STR41##                                                                     ##STR42##                                                                             Phos-                                                                Ex.      phonate       Tempera-                                                                            trans:                                                                             Crude                                       No.                                                                              Solvent                                                                             (eq.)                                                                              Base     ture  cis  Yield                                       __________________________________________________________________________    20 THF   1.10 LiHMDS   -78° C. to                                                                    8:1 110%                                                               r.t.                                                   21 THF   1.10 NaH      -78° C. to                                                                   14:1 107%                                                               r.t.                                                   22 THF   1.10 KOC(CH.sub.3).sub.2                                                                    -78° C. to                                                                   26:1  95%                                                      CH.sub.2 CH.sub.3                                                                      r.t.                                                   23 THF   1.10 KOC(CH.sub.3).sub.2                                                                    0° C. to                                                                     19:1  96%                                                      CH.sub.2 CH.sub.3                                                                      r.t.                                                   24 THF   1.02 KOC(CH.sub.3).sub.2                                                                    -78° C. to                                                                   18:1  91%                                                      CH.sub.2 CH.sub.3                                                                      r.t.                                                   25 CH.sub.3 CN                                                                         1.05 LiCl/DBU r.t.  36:1 101%                                        __________________________________________________________________________

EXAMPLE 26[2(S),3aα,4β,7β,7aα,]-Hexahydro-2-(1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione

Furan (222 ml, 3.06M) was added under Ar to maleic anhydride (50.0 g,0.510M) that had been broken up into small pieces in a 2-L 3-neckedflask (dried at 125°) equipped with a mechanical stirrer and chilled ina cold water bath. After the addition, the flask was stoppered and themaleic anhydride was dissolved by stirring. The solution was let standfor 22 hrs without stirring. A crystalline mass formed.

n-BuOAc (500 ml) was added under Ar to form a suspension. The mixturewas chilled in an ice-bath. A mixture of triethylamine (TEA) (71.1 ml,0.510M), and (S)-(-)-α-methylbenzylamine (65.7 ml, 0.510M) was addeddropwise over 15 min so that the temperature of the reaction mixturenever rose above 10°. The suspension dissolved after stirring for 10min, the ice-bath was removed and 5% Pd/C (7.19 g) was added. H₂ wassparged through the mixture. The hydrogenation was followed by TLC(silica gel, EtOAc/HOAc/MeOH 8:1:1, visualized by KMnO₄ spray). After2.5 hrs, ¹ H NMR (CDCl₃, 1 drop of the reaction mixture filtered andwashed with CDCl₃ through Celite into the NMR tube) showed no olefin.The excess H₂ was removed by sparging with N₂ for 15 min. The catalystwas filtered through Celite and washed with n-BuOAc (4×10 ml) directlyinto a 1-L distillation flask.

The filtrate was partially distilled through a short path still with aheating mantle equipped with a thermocouple. Enough heat (mantel temp.165°) was applied to distill out 250 ml distillate (furan and TEA) at bp88°-122° over 30 min. The mantle temperature (thermocouple) wasmaintained at ˜155° so that another 140 ml distillate came over at ˜124°over 1.5 hrs. TLC (silica gel, EtOAc/HOAc/MeOH 8:1:1, visualized byceric ammonium molybdate) showed disappearance of acid amides with 2spots at R_(f) s 0.28 and 0.34 and title compound at R_(f) 0.85. Aftercooling to room temperature, the residue in the pot (˜400 ml) was washedinto a 1-L separatory funnel with EtOAc and washed with 1N HCl (300 ml).During the washing, a voluminous precipitate formed. It was redissolvedby adding EtOAc (300 ml). The aqueous layer was separated and theorganic layer was washed with water (300 ml), 5% NaHCO₃ (300 ml), brine(100 ml), and dried (MgSO₄). Darco G-60 (14 g) was added and stirred for15 min, filtered through Celite, and washed with EtOAc (4×10 ml). Thefiltrate was evaporated at a bath temperature of 50° until the residueweighed 300 g. The residue was heated on the steam bath while slowlyadding heptane (950 ml). Crystals started to form immediately. The hotmixture was allowed to cool to room temperature and let stand for 6 hrs.The crystals were collected on a filter (25-50μ) with their own motherliquor, washed with cold heptane, and dried overnight at roomtemperature. The white crystals of title compound weighed 117.64 g(85%), mp. 108°-9°, [α]_(D) -67° [c=5.08, CHCl₃ ]. The so-formed imidewas used to prepare aldehyde as described in Example 1.

EXAMPLE 27[2(S),3aα,4β,7β,7aα]-Hexahydro-2-(1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione

A. (S)-(-)-α-Methylbenzylmaleamic acid

    ______________________________________                                        Material   F.W.      Moles   Equiv.  Amount                                   ______________________________________                                        Maleic Anhydride                                                                          98.06    0.102   1.0     10.00 g                                  MBA*       121.18    0.107   1.05    13.80 mls                                Acetonitrile                                                                             --        --      --      100.0 mls                                ______________________________________                                         *(S)-(-)-α-methylbenzylamine                                       

A 250 mL three-necked flask fitted with mechanical stirrer, condenserand thermocouple was charged with maleic anhydride and acetonitrile.

The (S)-(-)-α-methylbenzylamine was added dropwise via an additionfunnel (over a fifteen minute period) with stirring to the maleicanhydride solution. The reaction to form the title compound was completein three hours according to HPLC.

B. N-(S )-(-)-α-Methylbenzylmaleimide

    ______________________________________                                        Material     F.W.     Moles   Equiv. Amount                                   ______________________________________                                        Part A maleamic acid  --      1.0    100.0 mls                                                                     approx.                                  Diisopropylamine                                                                           101.19   0.204   2.0    28.58 mls                                HMDS*        161.14   0.204   2.0    43.00 mls                                ______________________________________                                         *1,1,1,3,3,3-Hexamethyldisilazane                                        

Diisopropylamine was added to the stirring colorless reaction solutionvia an addition funnel followed by a rapid addition of the HMDS.

The reaction solution was heated to reflux (76.0° C.) and refluxing wasmaintained for 18 hours. The reaction solution changed from a colorlesssolution to a dark wine solution. The reaction to form the titlecompound was judged complete via HPLC.

The reaction solution was allowed to cool to room temperature and theacetonitrile was removed in vacuo giving a wine colored oil. Ethanol (50ml) and 1N HCl (50 ml) were added to the oil and the solution wasstirred at 45° C. for ten minutes. The ethanol was removed in vacuo andthe wine solution was extracted with methylene chloride (100 ml). Theorganic layer was washed with saturated sodium bicarbonate (50 ml),brine (50 ml) and dried over anhydrous magnesium sulfate. The methylenechloride was removed in vacuo to give a dark wine oil (13.09 g, 63.8M %yield). This oil was purified on a pad of silica gel eluting withhexane/ethyl acetate 7:3 to give the title compound as a pale amber oil(10.71 g, 52.2M % yield).

C.[2(S),3aα,4β,7β,7aα]-Hexahydro-2-(1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione

AlCl₃ (0.199 g, 1.49 mM) was added to Part B imide (1.0 g, 4.98 mM) andfuran (1.08 ml, 14.9 mM) stirred in CH₂ Cl₂ (16.6 ml) chilled in anice-bath under an argon atmosphere. After 15 min the ice-bath wasremoved and the mixture was stirred overnight at room temperature. Ablack precipitate was formed. TLC (silica gel, EtOAc-Hexane 1:1,visualized by UV and ceric ammonium molybdate) showed disappearance ofthe imide R_(f) 0.71 and appearance of the product at R_(f) 0.44. EtOAc(20 ml) and 1N HCl (20 ml) were added and stirred for 10 min. Themixture was filtered through Celite to remove a brown solid which waswashed on the filter with EtOAc (100 ml). The filtrate was added to aseparatory funnel, the aqueous layer separated, and the organic layerwashed with 1N HCl (20 ml), water (20 ml), 5% NaHCO₃ (20 ml), brine (10ml), and dried (MgSO₄ for 5 min). Darco G-60 (0.5 g) was added andstirred for 30 min. The mixture was filtered through Celite andevaporated to ˜25 ml. The residue was washed with 25 ml EtOAc into ahydrogenation flask containing 5% Pd/C (0.1 g). H₂ was sparged throughthe mixture for 1 hr. N₂ was sparged for 15 min. to remove excess H₂.Darco G-60 (0.5 g) was added and stirred for 30 min. The mixture wasfiltered through Celite, washed with EtOAc, and evaporated to give 1.27g (94% crude yield).

The semisolid residue was dissolved in EtOAc (1.5 ml) and heptane (10ml) by heating on the steam bath. The solution was let stand at roomtemperature for 2 hrs and at 0° for 3 hrs. The crystals were filtered,washed with cold hexane and dried overnight under vacuum to yield 1.12 g(83%) of the title compound, mp. 107°-9°.

Anal. calcd. for C₁₆ H₁₇ NO₃ (271.3) C, 70.83; H, 6.32; N, 5.16; H₂ O0.00 Found: C, 70.88; H, 6.25; N, 5.19; H₂ O 0.01 (KF)

The title intermediate was employed to prepare the aldehyde as describedin Example 1.

EXAMPLE 28[2(S),3aα,4β,7β,7aα]-3a,4,7,7a-Tetrahydro-2-(1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione

AlCl₃ (0.199 g, 1.49 mM) was added to a solution of imide (prepared asdescribed in Example 27, Part B) (1.0 g, 4.98 mM) and furan (1.08 ml,14.9 mM) in CH₂ Cl₂ (16.6 ml) chilled in an ice-bath under an argonatmosphere. After stirring for 15 min. the ice-bath was removed and themixture stirred overnight at room temperature. A black precipitate wasformed. TLC (silica gel, EtOAc-hexane 1:1, visualized by UV and cericammonium molybdate) showed disappearance of Example 27 Part B imide(R_(f) 0.71) and appearance of the title compound at R_(f) 0.44. EtOAc(20 ml) and 1N HCl (20 ml) were added and stirred for 10 min. Themixture was filtered through Celite from a brown solid which was washedon the filter with EtOAc (100 ml). The organic layer was washed with 1NHCl (20 ml), water (20 ml), 5% NaHCO₃ (20 ml), brine (10 ml), and dried(MgSO₄ for 5 min). Darco G-60 (0.5 g) was added and stirred for 30 min.The mixture was filtered through Celite and evaporated to a foam whichsolidified to give 1.36 g (99% crude yield estimated from NMR, contained10% EtOAc).

The crude product was dissolved in 10% EtOAc/hexane and filtered througha pad of silica gel and then chromatographed on silica gel (25×300 mmcolumn). Product was eluted with EtOAc/hexane (1:4) collecting 50 mlfractions. Pure fractions by TLC (silica gel, EtOAc/hexane 1:1,visualized by UV and ceric ammonium molybdate, R_(f) 0.44) werecollected and evaporated to yield 1.18 g (88% ) of the title compound,mp. 101°-3°, [α]_(D) =-70.0° (c=1.5, CHCl₃).

Anal. calcd. for C₁₆ H₁₅ NO₃ (269.3) C, 71.36; H, 5.61; N, 5.20; H₂ O0.00 Found: C, 71.26; H, 5.61: N, 5.24; H₂ O 0.02 (KF)

The title imide was hydrogenated to the corresponding hexahydro compoundas described in Example 27 and employed to prepare aldehyde as describedin Example 1.

EXAMPLE 29 (S)-(-)-α-Methylbenzylmaleimide

    ______________________________________                                        Material  F.W.      Moles   Equiv.  Amount                                    ______________________________________                                        Maleamic acid*                                                                          219.24    0.245   1.0     53.8 g                                    HMDS**    161.40    0.758   3.1     160.0 ml                                  Acetonitrile                                                                            --        --      --      1500 ml                                   ______________________________________                                         *(S)-(-)-α-methylbenzylmaleamic acid                                    **1,1,1,3,3,3Hexamethyldisilazane                                        

A 2000 mL three necked flask fitted with mechanical stirrer, condenserand thermocouple was charged with 53.8 grams of Example 27 Part Amaleamic acid, 1500 mls. of acetonitrile and 160 mls. of HMDS.

The above solution was refluxed for 48 hours. The reaction was judged tobe complete by the absence of starting maleamic acid by HPLC.

The pink reaction solution was cooled to room temperature andacetonitrile was removed in vacuo. The resulting oil was dissolved inethyl acetate (500 mls) and washed with 50 mls. of a 1N HCl solutionfollowed by 100 mls. of a saturated bicarbonate solution. The richorganic layer was washed with a saturated brine solution and dried overmagnesium sulfate. The removal of the ethyl acetate in vacuo afforded36.0 grams of title compound. 72.9M % yield.

The reaction solution was allowed to cool to room temperature and theacetonitrile was removed in vacuo giving a wine colored oil. Ethanol (50ml) and 1N HCl (50 ml) were added to the oil and the solution wasstirred at 45° C. for ten minutes. The ethanol was removed in vacuo andthe wine solution was extracted with methylene chloride (100 ml). Theorganic layer was washed with saturated sodium bicarbonate (50 ml),brine (50 ml) and dried over anhydrous magnesium sulfate. The methylenechloride was removed in vacuo to give a dark wine oil (13.09 g, 63.8M %yield). This oil was purified on a pad of silica gel eluting withhexane/ethyl acetate 7:3 to give the title compound as a pale amber oil(10.71 g, 52.2M % yield).

The title compound was employed to prepare the Examples 27 and 28compounds.

EXAMPLE 30[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)-benzaldehyde

A. (S)-1-[2-(Acetyloxy)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-2,5-dione##STR43##

1,3-Bis(trimethylsilyl)urea (0.745 g, 3.65 mM) was added to(S)-(+)-2-phenylglycinol (0.5 g, 3.65 mM) dissolved in THF (10 ml,distilled from Na/benzophenone). The mixture was refluxed for 1 hr. Aprecipitate formed. Maleic anhydride (0.376 g, 3.83 mM) was added andthe mixture was refluxed for 0.5 hr. H₂ P (66 μl, 3.65 mM) was added tothe cooled mixture and stirred for 30 min. to form the intermediate##STR44## which was not recovered from the reaction mixture.Tetrabutyl-ammonium fluoride (TBAF•3H₂ O, 0.115 g, 0.365 mM), aceticanhydride (Ac₂ O) (3.44 ml, 36.5 mM), and TEA (3.0 ml, 21.9 mM) wereadded and the mixture refluxed for 2.5 hrs. After cooling to roomtemperature, H₂ O (15 ml) was added and stirred for 1 hr. The reactionmixture was taken up in EtOAc (75 ml), washed with water (2×50 ml), 5%NaHCO₃ (50 ml), brine (25 ml), dried (MgSO₄), and evaporated to a blackoil: 0.88 g. The oil was Kugalrohr distilled under vacuum (˜0.3 mm),oven temperature 110°-30°, giving the title compound as a colorless oil:0.79 g (83% yield). TLC (silica gel, EtOAc/hexane 7:3 visualized with UVand KMnO₄) showed the product as one spot at R_(f) 0.60.

Calcd. for C₁₄ H₁₃ NO₄ (259.26) C, 64.86; H, 5.05; N, 5.40 Found: C,65.15; H, 5.05; N, 5.31; H₂ O 0.00 (KF)

B. [2(S),3aα,4β,7β,7aα]-2-[2-(Acetyloxy)-1-phenylethyl]-3a,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione ##STR45##

Tin chloride (2.90 ml, 2.90 mM, 1.0M in CH₂ Cl₂) was added by syringe to10 ml CH₂ Cl₂ at room temperature under argon. Part A compound (0.5 g,1.93 mM) in 1 ml CH₂ Cl₂ was added and then furan (0.70 ml, 9.65 mM) wasintroduced. After 6 hours another 0.70 ml furan was added and themixture stirred overnight. The mixture turned brown and a precipitateformed. The mixture was taken up in EtOAc (75 ml)/1N HCl (25 ml). It wasfiltered to remove the brown insoluble material. The layers wereseparated, and the EtOAc layer was washed with 1N HCl (25 ml), water (25ml), 5% NaHCO₃ (25 ml), brine (10 ml), dried (MgSO₄), and evaporated toa yellow foam: 0.681 g.

The foam was taken up in 30 ml warm MeOH, stirred with 5 g charcoal for15 min, filtered through Celite, and evaporated to a slightly coloredoil: 0.55 g. The oil was triturated with 3 ml MeOH. Crystals formedimmediately. After standing at 0° for 1 hour, the crystals werefiltered, washed with cold MeOH (2×1 ml) and dried under vacuumovernight to give the title compound: 0.47 g (75%), mp. 117°-9°, [α]_(D)+14.5° (c=1, CHCl₃).

Anal. calcd. for C₁₈ H₁₇ NO₅ •0.1 H₂ O (MW 327.32/329.2) C, 65.67; H,5.27; N, 4.25; H₂ O 0.57 Found: C, 65.75; H, 5.07; N, 4.43; H₂ O 0.57(KF)

C.[2(S),3aα,4β,7β,7aα]-Hexahydro-2-(2-hydroxy-1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione ##STR46##

Part B compound (0.400 g, 1.22 mM) and 5% Pd/C (40 mg) were stirred inEtOAc (10 ml) and H₂ was sparged through the mixture for 1.2 hrs. TLC(silica gel, EtOAc/hexane 7:3 visualized with UV and KMnO₄) showed thePart B olefin and the saturated intermediate ##STR47## with the sameR_(f) 0.44. The olefin spot was KMnO₄ positive while the spot for thesaturated intermediate (UV positive) from the reaction mixture wasnegative. N₂ was sparged through the mixture for 15 min to remove excessH₂. The catalyst was filtered through Celite and washed with EtOAc (4×2ml). The filtrate was evaporated to an oil which solidified on standingafter 2 days to saturated intermediate as fine white needles: 415 mg(quan. yield), mp. 96°-8°.

The above solid saturated intermediate (0.360 g, 1.06 mM) was dissolvedin MeOH (10 ml) and K₂ CO₃ (15 mg) was added and stirred for 4 hrs. TheK₂ CO₃ gradually dissolved. TLC (silica gel, EtOAc/hexane 7:3,visualized with UV and ceric ammonium molybdate) showed disappearance ofsaturated intermediate and appearance of a spot for the title compoundat R_(f) 0.20. MeOH was evaporated and the residue was taken up in EtOAc(25 ml) and washed with 1N HCl (10 ml), H₂ O (10 ml), 5% NaHCO₃ (10 ml),and brine (10 ml), dried (MgSO₄), and evaporated: 0.29 g.

The residue was dissolved in hot EtOAc (1.5 ml) and hexane (3 ml) wasadded with heating. The solution was let stand at room temperature for 3hrs and at 0° for 2 hrs. The crystals were filtered, washed with coldhexane, and dried under vacuum overnight to give the title compound as awhite solid: 0.25 g (82%), mp 118°-9°, [α]_(D) -16.0° (c=1.3, CHCl₃).

Anal. calcd. for C₁₆ H₁₇ NO₄, (MW 287.1) C, 66.89; H, 5.96; N, 4.88Found: C, 66.83; H, 6.01; N, 5.06; H₂ O 0.00 (KF)

D.[2S-(2α,3aα,4β,7β,7aα)]-2-(Octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)-benzaldehyde

Following the procedure of Example 1 Parts C and D, the titlebenzaldehyde is obtained which is used in the procedure outlined inExample 6 to obtain the final product of Example 6.

EXAMPLE 30A

(S)-1-[2-(Acetyloxy)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-2,5-dione(Alternative Synthesis ) ##STR48##

Maleic anhydride (358 mg, 3.65 mM) was added to (S)-(+)-2-phenylglycinol(500 mg, 3.65 mM) dissolved in 5 ml THF stirred under Ar. A precipitateformed immediately but redissolved after 1 hr. The mixture was stirredovernight. TLC (silica gel, EtOAc/HOAc 95:5) showed two spots, theproduct R_(f) 0.34, and a lower R_(f) spot, R_(f) 0.09. The THF wasevaporated, and the residue was dissolved in 6 ml hot CH₂ Cl₂. Crystalsformed almost immediately in the hot mixture which was let stand at 5°for 2 hrs. The crystals were filtered, washed with cold CH₂ Cl₂, anddried under vacuum to give the title compound: 600 mg (70%), mp.131°-2°. ##STR49##

Acetic anhydride (5.38 ml, 57.1 mM) and triethylamine (7.94 ml, 57.1 mM)were added to the Part A amide acid (2.5 g, 11.4 mM) stirred in 20 mlTHF. The mixture was refluxed in an 85° oil bath for 2.5 hrs (TLC:silica gel, EtOAc/HOAc 95:5, SM R_(f) 0.34, product 0.71; the SMdisappeared and an anhydride intermediate (R_(f) 0.41) formed whichdisappeared into the product as the reaction proceeded). The mixture wasallowed to cool to room temperature, 20 ml H₂ O was added, and themixture stirred for 1 hr to hydrolyze any anhydride. The mixture wastaken up in 125 ml EtOAc, washed with 1N HCl (50 ml), H₂ O (50 ml), 5%NaHCO₃ (50 ml), and brine (25 ml), and then dried (MgSO₄) and evaporatedto give a black oil, 2.83 g.

The oil was chromatographed on silica gel (50×160 mm) eluted with 500 ml10% EtOAc/Hexane and 500 ml 20% EtOAc/Hexane collecting 40 ml fractions.Pure fractions by TLC (silica gel, EtOAc/Hexane, 4:6, R_(f) 0.37) werecombined and evaporated to give the title compound in the form of aslightly colored oil: 2.01 g (69%).

EXAMPLE 31[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, magnesium (2:1) salt

Example 6 compound (3.0 g, 6.82 mmol) was dissolved in 50 mL MeOH at 40°C. and the warm solution was poured into a mechanically stirred slurryof (0.504 g, 12.5 mmol) in 50 mL water preheated at 40° C. under argon.MeOH (50 mL) was added to the reaction mixture. The pH of the suspensionwas 6. The temperature of the mixture was maintained at 40° C. The pH ofthe mixture rose to 9.5 over 15 min. The warm bath was removed and afterstirring for 15 min. the mixture was filtered through a membrane filter(Rainin Nylon-66 filter 0.45 μm). The filter cake was washed with 15 mLmixture of MeOH/H₂ O (2:1) and the solvent was evaporated on a rotaryevaporator at 35° C. The product was redissolved in 15 mL MeOH andevaporated to dryness. The product was dried further under vacuumovernight to give 3.03 g (yield 97.4%) of the title magnesium salt, mp142°-45° C., [α]_(D) =+8.1° (c=1, MeOH).

Analysis cald for (C₂₅ H₃₁ N₂ O₅)₂ Mg•0.97 H₂ O; MW 903.38/920.81 C,65.21; H, 7.00; N, 6.09; Mg, 2.64; H₂ O, 1.90 Found: C, 65.07; H, 7.03;N, 5.92; Mg, 2.80; H₂ O 1.90 (KF)

What is claimed is:
 1. A method for preparing a carboxylic acidintermediate of the structure ##STR50## which comprises providing analdehyde of the structure ##STR51## treating the above aldehyde with atrialkylphosphonic acid, ester or diester thereof, or a magnesium saltof a monoalkyl malonate of the structure ##STR52## where R^(a) is loweralkyl, to form an ester of the structure ##STR53## and subjecting theabove ester to hydrogenation by treating the ester with hydrogen in thepresence of a hydrogenation catalyst, to form the carboxylic acidintermediate.
 2. The method as defined in claim 1 wherein the aldehydeis reacted with a trialkylphosphonic acid ester of the structure##STR54## wherein alkyl and alkyl' may be the same or different.
 3. Themethod as defined in claim 2 wherein the aldehyde and phosphonic acidester are reacted in a Horner-Emmons reaction wherein the reaction takesplace in the presence of a base which is1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or Hunig's base and an alkalimetal salt or an alkaline earth metal salt.
 4. The method as defined inclaim 2 wherein the aldehyde and phosphonic acid ester are reacted in aHorner-Emmons reaction wherein the reaction takes place in the presenceof sodium hydride, lithiumbis(trimethylsilyl)amide, or potassiumt-amylate.
 5. The method as defined in claim 1 wherein the startingaldehyde is in substantially enantiomerically pure form.